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The BMP pathway: A unique tool to decode the origin and progression of leukemia

  • Author Footnotes
    * FZ and MF-V contributed equally to this work.
    Florence Zylbersztejn
    Footnotes
    * FZ and MF-V contributed equally to this work.
    Affiliations
    Centre National de la Recherche Scientifique Unité Mixte de Recherche 5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France

    Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France

    Université de Lyon, 69000, Lyon, France

    Department of Signaling of Tumor Escape, Lyon, France
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  • Author Footnotes
    * FZ and MF-V contributed equally to this work.
    Mario Flores-Violante
    Footnotes
    * FZ and MF-V contributed equally to this work.
    Affiliations
    Centre National de la Recherche Scientifique Unité Mixte de Recherche 5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France

    Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France

    Université de Lyon, 69000, Lyon, France

    Department of Signaling of Tumor Escape, Lyon, France
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  • Thibault Voeltzel
    Affiliations
    Centre National de la Recherche Scientifique Unité Mixte de Recherche 5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France

    Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France

    Université de Lyon, 69000, Lyon, France

    Department of Signaling of Tumor Escape, Lyon, France
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  • Franck-Emmanuel Nicolini
    Affiliations
    Centre National de la Recherche Scientifique Unité Mixte de Recherche 5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France

    Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France

    Université de Lyon, 69000, Lyon, France

    Department of Signaling of Tumor Escape, Lyon, France

    Centre Léon Bérard, 69000 Lyon, France
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  • Sylvain Lefort
    Affiliations
    Centre National de la Recherche Scientifique Unité Mixte de Recherche 5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France

    Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France

    Université de Lyon, 69000, Lyon, France

    Department of Signaling of Tumor Escape, Lyon, France
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  • Véronique Maguer-Satta
    Correspondence
    Offprint requests to:CRCL, U1052-UMR5286, 28 Rue Laennec, 69373 Cedex 08, Lyon, France;
    Affiliations
    Centre National de la Recherche Scientifique Unité Mixte de Recherche 5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France

    Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France

    Université de Lyon, 69000, Lyon, France

    Department of Signaling of Tumor Escape, Lyon, France
    Search for articles by this author
  • Author Footnotes
    * FZ and MF-V contributed equally to this work.
Open ArchivePublished:February 22, 2018DOI:https://doi.org/10.1016/j.exphem.2018.02.005

      Highlights

      • Intrinsic and extrinsic bone morphogenic protein (BMP) signaling alterations promote cancer stem cell (CSC) features.
      • Under treatment, BMP alterations evolve independently of the oncogene.
      • Leukemic and nonleukemic BMP deregulations drive resistance and constitute therapeutic targets.
      The microenvironment (niche) governs the fate of stem cells (SCs) by balancing self-renewal and differentiation. Increasing evidence indicates that the tumor niche plays an active role in cancer, but its important properties for tumor initiation progression and resistance remain to be identified. Clinical data show that leukemic stem cell (LSC) survival is responsible for disease persistence and drug resistance, probably due to their sustained interactions with the tumor niche. Bone morphogenetic protein (BMP) signaling is a key pathway controlling stem cells and their niche. BMP2 and BMP4 are important in both the normal and the cancer context. Several studies have revealed profound alterations of the BMP signaling in cancer SCs, with major deregulations of the BMP receptors and their downstream signaling elements. This was illustrated in the hematopoietic system by pioneer studies in chronic myelogenous leukemia that may now be expanded to acute myeloid leukemia and lymphoid leukemia, as reviewed here. At diagnosis, cells from the leukemic microenvironment are the major providers of soluble BMPs. Conversely, LSCs display altered receptors and downstream BMP signaling elements accompanied by altered functional responses to BMPs. These studies reveal the role of BMPs in tumor initiation, in addition to their known effects in later stages of transformation and progression. They also reveal the importance of BMPs in fueling cell transformation and expansion by overamplifying a natural SC response. This mechanism may explain the survival of LSCs independently of the initial oncogenic event and therefore may be involved in resistance processes.

      Graphical Abstract

      During embryogenesis and development, the fate of stem cells (SCs) is guided by intrinsic and environmental cues, such as surrounding cells, matrix, and soluble factors. During cancer development, the maintenance and evolution of cancer stem cells (CSCs) also depends on their microenvironment. This has been particularly demonstrated in the hematological field, where the differentiation hierarchy from hematopoietic stem cells (HSCs) is a model and in which the existence of CSCs was first shown [
      • Maguer-Satta V.
      The stem cell niche: the black master of cancer.
      ,
      • Bonnet D.
      • Dick J.E.
      Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.
      ,
      • Eaves C.J.
      Hematopoietic stem cells: concepts, definitions, and the new reality.
      ,
      • Valent P.
      • Bonnet D.
      • De Maria R.
      • et al.
      Cancer stem cell definitions and terminology: the devil is in the details.
      ]. Among the soluble molecules involved in SC fate, the bone morphogenetic proteins (BMPs) have been shown to regulate self-renewal and differentiation during development [
      • Hogan B.L.
      Bone morphogenetic proteins: multifunctional regulators of vertebrate development.
      ] and are emerging as potential regulators of CSCs [
      • Caja L.
      • Kahata K.
      • Moustakas A.
      Context-dependent action of transforming growth factor beta family members on normal and cancer stem cells.
      ,
      • Bosukonda A.
      • Carlson W.D.
      Harnessing the BMP signaling pathway to control the formation of cancer stem cells by effects on epithelial-to-mesenchymal transition.
      ,
      • Lee J.
      • Son M.J.
      • Woolard K.
      • et al.
      Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells.
      ].
      BMP proteins belong to the transforming growth factor beta (TGFβ) superfamily of proteins, including TGFβ, activin, inhibin, growth differentiation factor (GDF), Nodal, Lefty, and anti-Müllerian hormone [
      • Guo X.
      • Wang X.F.
      Signaling cross-talk between TGF-beta/BMP and other pathways.
      ,
      • Miyazono K.
      • Kamiya Y.
      • Morikawa M.
      Bone morphogenetic protein receptors and signal transduction.
      ]. Although they belong to the same family of proteins, BMPs and TGFβ are often reported to display opposite effects on cell regulation. Moreover, even if BMP and GDF have high sequence homology [
      • Katoh Y.
      • Katoh M.
      Comparative integromics on BMP/GDF family.
      ], they also have different properties and functions [
      • Rider C.C.
      • Mulloy B.
      Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists.
      ]. BMP elements, initially described in bone formation, are now largely documented as being associated with the biology of a large number of organ systems, from embryonic to adult tissues, and are involved in proliferation, differentiation, and apoptosis of SCs. This major role in several biological processes and tissue homeostasis is illustrated by the fact that lack of soluble BMPs or BMP receptors is lethal or induces various severe pathologies [
      • Wang R.N.
      • Green J.
      • Wang Z.
      • et al.
      Bone morphogenetic protein (BMP) signaling in development and human diseases.
      ].

      BMP signaling pathway

      According to phylogenic trees, BMPs can be clustered into groups: BMP2/4, BMP5/6/7/8, BMP9/10, and the GDF 5/6/7 (Table 1) [
      • Rider C.C.
      • Mulloy B.
      Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists.
      ]. BMP2 and BMP4, which present structural homologies (Fig. 1), are secreted as precursor molecules and then cleaved by extracellular proteins such as Furin to obtain a mature protein (Fig. 2) [
      • Sopory S.
      • Nelsen S.M.
      • Degnin C.
      • Wong C.
      • Christian J.L.
      Regulation of bone morphogenetic protein-4 activity by sequence elements within the prodomain.
      ,
      • Harrison C.A.
      • Al-Musawi S.L.
      • Walton K.L.
      Prodomains regulate the synthesis, extracellular localisation and activity of TGF-beta superfamily ligands.
      ,
      • Leighton M.
      • Kadler K.E.
      Paired basic/furin-like proprotein convertase cleavage of pro-BMP-1 in the trans-Golgi network.
      ]. These active proteins form homocomplexes or heterocomplexes, which bind to receptor complexes and induce cell transduction (Table 1) [
      • Marom B.
      • Heining E.
      • Knaus P.
      • Henis Y.I.
      Formation of stable homomeric and transient heteromeric bone morphogenetic protein (BMP) receptor complexes regulates Smad protein signaling.
      ]. The BMP canonical pathway requires BMP type I receptor activation (BMPR1a/ALK3, BMPR1b/ALK6, or ACTRIa/ALK2), which bind and are phosphorylated by BMPR2 [
      • Miyazono K.
      • Kamiya Y.
      • Morikawa M.
      Bone morphogenetic protein receptors and signal transduction.
      ,
      • Nohe A.
      • Keating E.
      • Knaus P.
      • Petersen N.O.
      Signal transduction of bone morphogenetic protein receptors.
      ,
      • Yadin D.
      • Knaus P.
      • Mueller T.D.
      Structural insights into BMP receptors: Specificity, activation and inhibition.
      ]. This phosphorylation leads to further SMAD1/5/8 phosphorylation, resulting in BMP activity as a transcription factor [
      • Miyazono K.
      • Miyazawa K.
      Id: a target of BMP signaling.
      ,
      • Miyazono K.
      • Maeda S.
      • Imamura T.
      BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk.
      ,
      • Ampuja M.
      • Kallioniemi A.
      Transcription factors-Intricate players of the bone morphogenetic protein signaling pathway.
      ]. Alternatively, BMP can activate noncanonical pathways such as APK [
      • Gallea S.
      • Lallemand F.
      • Atfi A.
      • et al.
      Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells.
      ], p38 [
      • Guicheux J.
      • Lemonnier J.
      • Ghayor C.
      • Suzuki A.
      • Palmer G.
      • Caverzasio J.
      Activation of p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation.
      ], ERK [
      • Fong D.
      • Bisson M.
      • Laberge G.
      • et al.
      Bone morphogenetic protein-9 activates Smad and ERK pathways and supports human osteoclast function and survival in vitro.
      ], JUNK [
      • Engel M.E.
      • McDonnell M.A.
      • Law B.K.
      • Moses H.L.
      Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription.
      ], PI3K [
      • Chen X.
      • Liao J.
      • Lu Y.
      • Duan X.
      • Sun W.
      Activation of the PI3K/Akt pathway mediates bone morphogenetic protein 2-induced invasion of pancreatic cancer cells Panc-1.
      ], and PKC [
      • Zhang Y.E.
      Non-Smad pathways in TGF-beta signaling.
      ].
      Table 1BMP family ligands and receptors
      BMP LigandAssociated Type I ReceptorAssociated Type II Receptor
      BMP2, BMP4BMPR1a,BMPR1bBMPR2, ActRIIa
      BMP5,BMP6,BMP7BMPR1a,BMPR1b, ALK1/2BMPR2, ActRIIa, ActRIIb
      BMP9,BMP10BMPR1a,BMPR-Ib,ALK1BMPR2, ActRIIa, ActRIIb
      GDF5,GDF6,GDF7BMPR2, ActRIIa,BMPR1a,BMPR1b
      Figure 1
      Figure 1Structure and protein domains of soluble human BMP2/4 and its associated receptors.
      BMP signaling regulation is controlled through extracellular, membrane, and intracellular elements (Fig. 2). Extracellular soluble antagonists such as Chordin [
      • Piccolo S.
      • Sasai Y.
      • Lu B.
      • De Robertis E.M.
      Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4.
      ,
      • Piccolo S.
      • Agius E.
      • Lu B.
      • Goodman S.
      • Dale L.
      • De Robertis E.M.
      Cleavage of Chordin by Xolloid metalloprotease suggests a role for proteolytic processing in the regulation of Spemann organizer activity.
      ], Follistatin [
      • Maguer-Satta V.
      • Bartholin L.
      • Jeanpierre S.
      • et al.
      Regulation of human erythropoiesis by activin A, BMP2, and BMP4, members of the TGFbeta family.
      ], FLRG [
      • Maguer-Satta V.
      Rimokh R. FLRG, member of the follistatin family, a new player in hematopoiesis.
      ], Noggin [
      • Zimmerman L.B.
      • De Jesús-Escobar J.M.
      • Harland R.M.
      The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4.
      ,
      • Groppe J.
      • Greenwald J.
      • Wiater E.
      • et al.
      Structural basis of BMP signalling inhibition by the cystine knot protein Noggin.
      ], Gremlin [
      • Hsu D.R.
      • Economides A.N.
      • Wang X.
      • Eimon P.M.
      • Harland R.M.
      The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities.
      ], Cerberus [
      • Shawlot W.
      • Deng J.M.
      • Behringer R.R.
      Expression of the mouse cerberus-related gene, Cerr1, suggests a role in anterior neural induction and somitogenesis.
      ], and Tolloid [
      • Scott I.C.
      • Blitz I.L.
      • Pappano W.N.
      • et al.
      Mammalian BMP-1/Tolloid-related metalloproteinases, including novel family member mammalian Tolloid-like 2, have differential enzymatic activities and distributions of expression relevant to patterning and skeletogenesis.
      ] bind BMPs and prevent their binding to the receptor, thus modifying the local concentration of the available ligand. Other BMP regulators act at the membrane level to either activate (Endoglin, Endofin, and RGM-Repulsive guidance family members) or inhibit (BAMBI: BMP and Activin membrane-bound inhibitor) the BMP pathway, according to the context, through direct binding with BMP (RGM) or both BMP and BMP receptor (Endoglin, BAMBI) [
      • Scherner O.
      • Meurer S.K.
      • Tihaa L.
      • Gressner A.M.
      • Weiskirchen R.
      Endoglin differentially modulates antagonistic transforming growth factor-beta1 and BMP-7 signaling.
      ]. BAMBI binds with type II receptors to prevent the formation of the molecular complex that transduces the signal [
      • Onichtchouk D.
      • Chen Y.G.
      • Dosch R.
      • et al.
      Silencing of TGF-beta signalling by the pseudoreceptor BAMBI.
      ]. Conversely, certain coreceptors of the BMPR (such as RGMa/b/c and DRAGON [
      • Babitt J.L.
      • Zhang Y.
      • Samad T.A.
      • et al.
      Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor.
      ,
      • Corradini E.
      • Babitt J.L.
      • Lin H.Y.
      The RGM/DRAGON family of BMP co-receptors.
      ]) associate with a preformed complex to enhance the BMP pathway. Finally, cytoplasmic SMAD6/7 molecules inhibit SMAD1/5/8 phosphorylation and therefore preclude complex formation with the SMAD4 cofactor; they also recruit SMAD ubiquitin ligases (SMURF1/2) to mediate their degradation [
      • Zhu H.
      • Kavsak P.
      • Abdollah S.
      • Wrana J.L.
      • Thomsen G.H.
      A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation.
      ]. Importantly, the mechanisms by which the BMP pathway regulate cell fate also depend on interactions and crosstalk with other signaling pathways such as TGFβ [
      • Caja L.
      • Kahata K.
      • Moustakas A.
      Context-dependent action of transforming growth factor beta family members on normal and cancer stem cells.
      ], Wnt/β-catenin [
      • Ille F.
      • Atanasoski S.
      • Falk S.
      • et al.
      Wnt/BMP signal integration regulates the balance between proliferation and differentiation of neuroepithelial cells in the dorsal spinal cord.
      ], Janus kinase (JAK)/signal transducer and activator of transcription (STAT) [
      • Ulloa L.
      • Doody J.
      • Massague J.
      Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway.
      ,
      • Jeanpierre S.
      • Nicolini F.E.
      • Kaniewski B.
      • et al.
      BMP4 regulation of human megakaryocytic differentiation is involved in thrombopoietin signaling.
      ], and Ca2+/calmodulin [
      • Rashid F.
      • Shiba H.
      • Mizuno N.
      • et al.
      The effect of extracellular calcium ion on gene expression of bone-related proteins in human pulp cells.
      ].
      Figure 2
      Figure 2Schematic representation of the BMP signaling pathway.

      Biological functions of the BMP pathway during normal hematopoiesis

      BMP molecules in the regulation of hematopoiesis have been documented as being involved in various levels of SC differentiation [
      • Bhardwaj G.
      • Murdoch B.
      • Wu D.
      • et al.
      Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation.
      ,
      • Fuchs O.
      • Simakova O.
      • Klener P.
      • et al.
      Inhibition of Smad5 in human hematopoietic progenitors blocks erythroid differentiation induced by BMP4.
      ,
      • Jay K.E.
      • Gallacher L.
      • Bhatia M.
      Emergence of muscle and neural hematopoiesis in humans.
      ,
      • Marshall C.J.
      • Thrasher A.J.
      The embryonic origins of human haematopoiesis.
      ,
      • Zon L.I.
      Self-renewal versus differentiation, a job for the mighty morphogens.
      ]. BMPs exhibit a highly important role in the formation of hematopoietic and endothelial precursors emerging from the ventral mesoderm [
      • Huber T.L.
      • Zhou Y.
      • Mead P.E.
      • Zon L.I.
      Cooperative effects of growth factors involved in the induction of hematopoietic mesoderm.
      ]. Indeed, BMP2 and BMP4, alone or in combination with Activin A, have been shown to be involved in the regulation of erythropoiesis in various models [
      • Huber T.L.
      • Zhou Y.
      • Mead P.E.
      • Zon L.I.
      Cooperative effects of growth factors involved in the induction of hematopoietic mesoderm.
      ,
      • Johansson B.M.
      • Wiles M.V.
      Evidence for involvement of activin A and bone morphogenetic protein 4 in mammalian mesoderm and hematopoietic development.
      ,
      • Wiles M.V.
      • Johansson B.M.
      Analysis of factors controlling primary germ layer formation and early hematopoiesis using embryonic stem cell in vitro differentiation.
      ,
      • Miyanaga Y.
      • Shiurba R.
      • Asashima M.
      Blood cell induction in Xenopus animal cap explants: effects of fibroblast growth factor, bone morphogenetic proteins, and activin.
      ,
      • Maeno M.
      • Mead P.E.
      • Kelley C.
      • et al.
      The role of BMP-4 and GATA-2 in the induction and differentiation of hematopoietic mesoderm in Xenopus laevis.
      ]. In particular, in Xenopus laevis embryos, ectopic expression of BMP4 results in the induction of several specific hematopoietic genes, such as transcription factors and the erythroid-specific globin [
      • Huber T.L.
      • Zhou Y.
      • Mead P.E.
      • Zon L.I.
      Cooperative effects of growth factors involved in the induction of hematopoietic mesoderm.
      ,
      • Maeno M.
      • Mead P.E.
      • Kelley C.
      • et al.
      The role of BMP-4 and GATA-2 in the induction and differentiation of hematopoietic mesoderm in Xenopus laevis.
      ,
      • Mead P.E.
      • Kelley C.M.
      • Hahn P.S.
      • Piedad O.
      • Zon L.I.
      SCL specifies hematopoietic mesoderm in Xenopus embryos.
      ,
      • Zhang C.
      • Evans T.
      BMP-like signals are required after the midblastula transition for blood cell development.
      ].
      Bmp2, Bmp4, Bmp7, Bmpr1a, and Bmpr2 knock-out mice therefore have a lethal phenotype due to a lack of formation of hematopoietic tissues or a defect in the development of mesoderm or endoderm [
      • Wang R.N.
      • Green J.
      • Wang Z.
      • et al.
      Bone morphogenetic protein (BMP) signaling in development and human diseases.
      ]. In vitro, BMP4 plays an important role in the induction of hematopoietic differentiation in human and murine embryonic stem cell models [
      • Johansson B.M.
      • Wiles M.V.
      Evidence for involvement of activin A and bone morphogenetic protein 4 in mammalian mesoderm and hematopoietic development.
      ,
      • Chadwick K.
      Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells.
      ]. In mice, BMP coreceptor expressions have been detected during hematopoietic system development in early immature cells that display hematopoietic and endothelial potential [
      • Borges L.
      • Iacovino M.
      • Koyano-Nakagawa N.
      • et al.
      Expression levels of endoglin distinctively identify hematopoietic and endothelial progeny at different stages of yolk sac hematopoiesis.
      ]. Indeed, the induction of endothelin-dependent hematopoiesis requires response to Bmp2 and Bmp4 modulation in the yolk sac. Moreover, a mouse knock-out model of Smad5 invalidation leads to a delayed lethal phenotype during development due to a yolk sac circulatory defect associated with an inhibition of progenitor expansion [
      • Chang H.
      • Huylebroeck D.
      • Verschueren K.
      • Guo Q.
      • Matzuk M.M.
      • Zwijsen A.
      Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects.
      ,
      • Yang X.
      • Castilla L.H.
      • Xu X.
      • et al.
      Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5.
      ]. Homozygous Bmp4-deleted mice display a lethal phenotype characterized by reduced extraembryonic mesoderm including blood islands [
      • Winnier G.
      • Blessing M.
      • Labosky P.A.
      • Hogan B.L.
      Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse.
      ]. More recently, it has been demonstrated that BMP pathway activation occurs in all hematopoietic cells during the hematopoiesis-emerging phase in aorta gonad mesonephros [
      • Crisan M.
      • Kartalaei P.S.
      • Vink C.
      • et al.
      BMP signalling differentially regulates distinct haematopoietic stem cell types.
      ]. Interestingly, in the following steps of the hematopoietic process, these HSCs could distinguish themselves as being BMP-positive or BMP-negative and generate a majority of cells no longer activated by this pathway. These findings suggest a role for the BMP signaling axis in the regulation of HSC heterogeneity and lineage output. The role of Bmpr1a in regulating adult HSC development has been studied in vivo by analyzing mutant mice with conditional inactivation. These mice have an increased number of spindle-shaped N-cadherin CD45.2 osteoblastic (SNO) cells, associated with an increased HSC number. This study showed that the Bmpr1a signaling pathway allows long-term HSC adhesion to SNO cells by the molecules N-cadherin and β-catenin and regulates the niche size [
      • Zhang J.
      • Niu C.
      • Ye L.
      • et al.
      Identification of the haematopoietic stem cell niche and control of the niche size.
      ].
      In human adult cells, phenotypic analysis revealed the expression of BMP receptors such as BMPR1a and BMPR1b and the expression of the effector elements of the canonical pathway, SMAD1/5/8, in CD34+CD38Lin cells [
      • Bhatia M.
      • Bonnet D.
      • Wu D.
      • et al.
      Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells.
      ]. Treatment of CD34+CD38 human cells with high concentrations of BMP2 and BMP7 blocks their proliferation while maintaining their immature phenotype. Conversely, treatment of the same subpopulation of cells with high concentrations of BMP4 maintains their ability to reconstitute immunodeficient mice. Conversely, low doses of BMP4 enhance cell proliferation rather than differentiation. In the same manner, CD34+ cells are expanded when treated with low doses of BMP7 without affecting their engraftment capacity in immunodeficient mice [
      • Su Y.H.
      • Cai H.B.
      • Ye Z.Y.
      • Tan W.S.
      BMP-7 improved proliferation and hematopoietic reconstitution potential of ex vivo expanded cord blood-derived CD34(+) cells.
      ]. In addition, BMP4 regulates homing of murine and human hematopoietic stem/progenitor cells through the direct regulation of Integrin-alpha4 expression in SMAD-independent p38 MAPK-mediated signaling [
      • Khurana S.
      • Buckley S.
      • Schouteden S.
      • et al.
      A novel role of BMP4 in adult hematopoietic stem and progenitor cell homing via Smad independent regulation of integrin-alpha4 expression.
      ]. BMP2 or Activin A treatment alone decreases the expression of GATA-2 and increases the expression of EPO-R on CD34+ cells. SMAD6 overexpression blocks erythropoiesis in vitro by transcriptional regulation of KLF1 and GATA-2 and indirectly participates in HSC maintenance by blocking the differentiation process [
      • Kang Y.J.
      • Shin J.W.
      • Yoon J.H.
      • et al.
      Inhibition of erythropoiesis by Smad6 in human cord blood hematopoietic stem cells.
      ]. Conversely, only simultaneous treatment of BMP4 with Activin A is able to modulate erythropoiesis in a Follistatin- and FLRG-mediated way [
      • Maguer-Satta V.
      • Bartholin L.
      • Jeanpierre S.
      • et al.
      Regulation of human erythropoiesis by activin A, BMP2, and BMP4, members of the TGFbeta family.
      ].
      In the murine system, BMP4 is able to induce erythrocyte differentiation of CD34+ cells in the presence of stem cell factor (SCF) and erythropoietin (EPO) [
      • Perry J.M.
      • Harandi O.F.
      • Paulson R.F.
      BMP4, SCF, and hypoxia cooperatively regulate the expansion of murine stress erythroid progenitors.
      ]. Comparatively, in human cells, BMP4 in combination with various hematopoietic cytokines, including EPO, is able to induce several blood lineages from other human tissues [
      • Jay K.E.
      • Gallacher L.
      • Bhatia M.
      Emergence of muscle and neural hematopoiesis in humans.
      ]. This unexpected cell fate has been demonstrated using human muscle and neural gestational tissue suspension cultured in a serum-free medium with interleukin (IL) 3, IL6, SCF, and FLT-3 ligand with addition of EPO and BMP4 [
      • Jay K.E.
      • Gallacher L.
      • Bhatia M.
      Emergence of muscle and neural hematopoiesis in humans.
      ]. Conversely, BMP4 alone is able to induce human megakaryopoiesis from CD34+ cells through the JAK/STAT and mammalian target of rapamycin pathways [
      • Zon L.I.
      Self-renewal versus differentiation, a job for the mighty morphogens.
      ]. These data clearly showed that, unlike the murine system and despite their very high protein sequence homology and similar use of BMPR signaling, BMP2- and BMP4-soluble molecules exhibit very distinct effects on human HSCs. Interestingly similar observations were made for BMP2 and BMP4 on the control of other human adult tissue stem cells such as mammary epithelial SCs [
      • Chapellier M.
      • Bachelard-Cascales E.
      • Schmidt X.
      • et al.
      Disequilibrium of BMP2 levels in the breast stem cell niche launches epithelial transformation by overamplifying BMPR1B cell response.
      ].

      BMP pathway in early phase of myeloid leukemia

      Although BMP signaling is an important element from embryogenesis to adult tissue homeostasis, deregulation of this signaling pathway is involved in several types of cancer, mainly during late stages of solid tumor evolution [
      • Caja L.
      • Kahata K.
      • Moustakas A.
      Context-dependent action of transforming growth factor beta family members on normal and cancer stem cells.
      ,
      • Wang R.N.
      • Green J.
      • Wang Z.
      • et al.
      Bone morphogenetic protein (BMP) signaling in development and human diseases.
      ,
      • Zhang L.
      • Ye Y.
      • Long X.
      • Xiao P.
      • Ren X.
      • Yu J.
      BMP signaling and its paradoxical effects in tumorigenesis and dissemination.
      ]. Alterations in the BMP pathway have also been reported in some hematogical diseases (Table 2). The existence of LSCs has been demonstrated in acute myeloid leukemia (AML), in which the deregulation of various signaling pathways in the bone marrow gives rise to an altered HSC with a strong capacity for self-renewal and quiescence for tumor initiation and growth [
      • Bonnet D.
      • Dick J.E.
      Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.
      ]. Moreover, the bone marrow niche appears to be a major factor in granting a protective microenvironment for LSCs, contributing to resistance against chemotherapy and patient relapse [
      • Maguer-Satta V.
      The stem cell niche: the black master of cancer.
      ,
      • Toofan P.
      • Wheadon H.
      Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis.
      ,
      • Wang J.C.
      • Dick J.E.
      Cancer stem cells: lessons from leukemia.
      ].
      Table 2BMP signaling pathway deregulation in hematological disorders
      Hematological DisorderTumor Microenvironment AlterationSoluble BMPSignaling ElementTarget Gene ModifiedReference(s)
      CMLHigh concentration soluble BMP2/BMP4BMP2/BMP4high BMPR1B p-SMAD 1/ 8TWIST-1
      • Toofan P.
      • Wheadon H.
      Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis.
      ,
      • Laperrousaz B.
      • Jeanpierre S.
      • Sagorny K.
      • et al.
      Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression.
      ,
      • Grockowiak E.
      • Laperrousaz B.
      • Jeanpierre S.
      • et al.
      Immature CML cells implement a BMP autocrine loop to escape TKI treatment.
      AMLUnknownBMP4BMP type IMIXL-1
      • Raymond A.
      • Liu B.
      • Liang H.
      • et al.
      A role for BMP-induced homeobox gene MIXL1 in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy.
      Acute megakaryoblastic leukemia (AMKL)UnknownBMP2/BMP4BMP type IId1
      • Gruber T.A.
      • Larson Gedman A.
      • Zhang J.
      • et al.
      An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.
      Acute promyelocytic leukemia (APL)UnknownBMP4/BMP6High receptor: BMPR1A/BMPR2/ACTRIIBId1/Id2
      • Topić I.
      • Ikić M.
      • Ivčević S.
      • et al.
      Bone morphogenetic proteins regulate differentiation of human promyelocytic leukemia cells.
      B-cell CLL (B-CLL)UnknownUnknownHigh receptor: BMPR1A/BMPR1B/BMPR2 (progressive increase with advanced stages)Not studied
      • Huse K.
      • Bakkebo M.
      • Walchli S.
      • et al.
      Role of Smad proteins in resistance to BMP-induced growth inhibition in B-cell lymphoma.
      ALLUnknownBMP2UnknownUnknown
      • Tesfai Y.
      • Ford J.
      • Carter K.W.
      • et al.
      Interactions between acute lymphoblastic leukemia and bone marrow stromal cells influence response to therapy.
      CLLUnknownUnknownSMAD 1/8Unknown
      • Witkowska M.
      • Majchrzak A.
      • Cebula-Obrzut B.
      • Wawrzyniak E.
      • Robak T.
      • Smolewski P.
      The distribution and potential prognostic value of SMAD protein expression in chronic lymphocytic leukemia.
      A unique and outstanding model to address key questions about LSCs is chronic myelogenous leukemia (CML). Indeed, this leukemia arises from the transformation of a true SC by the BCR-ABL oncogene. Without treatment, this disease evolves to an inexorable and fatal blast crisis. Our team revealed both intrinsic and extrinsic deregulation of the BMP pathway in CML as early as at the time of diagnosis in chronic phase [
      • Laperrousaz B.
      • Jeanpierre S.
      • Sagorny K.
      • et al.
      Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression.
      ]. We demonstrated higher expression levels of the BMPRIb receptor ALK6 in CD34+ cells, together with the existence of several molecular and functional alterations of the BMP pathway in chronic-phase CML. We also detected high concentrations of the soluble cytokines BMP2 and BMP4 produced exclusively by the tumor microenvironment. These alterations participate in the leukemic phenotype through their involvement in the survival of LSCs and in the expansion of leukemic myeloid progenitors. These data were further confirmed by other groups showing that BMP2/BMP4 and BMP7, together with their receptors and SMAD proteins, contribute to myeloid cell alteration, giving rise to CML LSCs [
      • Toofan P.
      • Wheadon H.
      Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis.
      ,
      • Gerber J.M.
      • Gucwa J.L.
      • Esopi D.
      • et al.
      Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations.
      ]. Our study demonstrated for the first time that very early transforming events initiate intrinsic deregulation of the BMP signaling pathway in stem cells. Indeed, introduction of the BCR-ABL oncogene results in an increase in BMPR1b cell membrane expression [
      • Laperrousaz B.
      • Jeanpierre S.
      • Sagorny K.
      • et al.
      Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression.
      ]. This deregulation is then specifically amplified in transformed cells by exposure to exogenous ligands such as BMP2/BMP4 provided by the SC microenvironment. Very surprisingly, we were able to decipher a similar mechanism in early phases of luminal breast cancer under the driving signals of estrogeno-mimetic pollutants [
      • Chapellier M.
      • Bachelard-Cascales E.
      • Schmidt X.
      • et al.
      Disequilibrium of BMP2 levels in the breast stem cell niche launches epithelial transformation by overamplifying BMPR1B cell response.
      ]. We demonstrated that bisphenol or radiation are able to initiate both intrinsic [
      • Clement F.
      • Xu X.
      • Donini C.F.
      • et al.
      Long-term exposure to bisphenol A or benzo(a)pyrene alters the fate of human mammary epithelial stem cells in response to BMP2 and BMP4, by pre-activating BMP signaling.
      ] and extrinsic [
      • Chapellier M.
      • Bachelard-Cascales E.
      • Schmidt X.
      • et al.
      Disequilibrium of BMP2 levels in the breast stem cell niche launches epithelial transformation by overamplifying BMPR1B cell response.
      ] deregulation of the BMP pathway in human mammary SCs and their surrounding stromal cells to initiate epithelial SC transformation [
      • Chapellier M.
      • Maguer-Satta V.
      BMP2, a key to uncover luminal breast cancer origin linked to pollutant effects on epithelial stem cells niche.
      ]. These data suggest that, in addition to already documented roles in the late stages of the disease, deregulation of the BMP pathway in both SCs and their surrounding microenvironment could constitute a more general mechanism during the early stages of cancer development.
      Later during disease progression, the CML leukemic bone marrow niche that produces high levels of BMPs can be suspected to be at the origin of secondary myelofibrosis. Indeed, this alteration, often reported upon CML evolution, represents an overproduction of extracellular matrix that has been previously attributed to excessive BMP cytokines within the BM niche [
      • Bock O.
      • Hoftmann J.
      • Theophile K.
      • et al.
      Bone morphogenetic proteins are overexpressed in the bone marrow of primary myelofibrosis and are apparently induced by fibrogenic cytokines.
      ].

      BMP pathway and resistance to treatment of LSCs

      Recently, two independent studies highlighted the important role played by the tumor niche in LSC resistance in CML. Using coculture experiments of stromal and CML cells, the impact of cell–cell interactions in resistance and in the regulation of cytokine production was identified [
      • Kumar A.
      • Bhattacharyya J.
      • Jaganathan B.G.
      Adhesion to stromal cells mediates imatinib resistance in chronic myeloid leukemia through ERK and BMP signaling pathways.
      ]. In this context, activation of the BMP-restricted phospho-SMAD 1/8 was identified in CML cells resistant to the highly specific BCR-ABL tyrosine kinase inhibitor. Moreover, our team revealed that alterations in the BMP pathway persist in the cells of chronic-phase CML patients under treatment, especially in the LSC compartment. Indeed, despite the effects of long-term specific BCR-ABL tyrosine kinase inhibitors, the BMP pathway remained deregulated at both the intrinsic and extrinsic leukemic levels, especially in resistant cells [
      • Grockowiak E.
      • Laperrousaz B.
      • Jeanpierre S.
      • et al.
      Immature CML cells implement a BMP autocrine loop to escape TKI treatment.
      ]. In addition, we showed that alterations in both LSCs and their surrounding stromal cells continue to evolve upon treatment and fuel LSC survival and treatment escape. In particular, continuous treatment pressure forced the development of a growth factor autocrine loop within the highly plastic LSC compartment. We showed that a fraction of bone marrow surviving LSCs then rely on the installation of this BMP4/BMPR1b autocrine loop that involves downstream TWIST-1 overexpression to escape treatment killing. Interestingly, we previously identified the embryonic basic helix-loop-helix transcription factor TWIST-1 to be overexpressed in immature compartments and to represent at diagnosis a predictive factor of CML treatment resistance [
      • Cosset E.
      • Hamdan G.
      • Jeanpierre S.
      • et al.
      Deregulation of TWIST-1 in the CD34+ compartment represents a novel prognostic factor in chronic myeloid leukemia.
      ]. TWIST-1 overexpression promotes cell growth, tumor-initiating properties, and drug resistance and increases clonogenic capacities in other myeloid leukemias [
      • Wang N.
      • Guo D.
      • Zhao Y.
      • et al.
      TWIST-1 promotes cell growth, drug resistance and progenitor clonogenic capacities in myeloid leukemia and is a novel poor prognostic factor in acute myeloid leukemia.
      ,
      • Merindol N.
      • Riquet A.
      • Szablewski V.
      • Eliaou J.F.
      • Puisieux A.
      • Bonnefoy N.
      The emerging role of Twist proteins in hematopoietic cells and hematological malignancies.
      ]. Interestingly, TWIST-1 can be a regulator or a target of the BMP pathway in different cell models [
      • Wu K.J.
      Direct activation of Bmi1 by Twist1: implications in cancer stemness, epithelial-mesenchymal transition, and clinical significance.
      ,
      • Hayashi M.
      • Nimura K.
      • Kashiwagi K.
      • et al.
      Comparative roles of Twist-1 and Id1 in transcriptional regulation by BMP signaling.
      ]. In the context of CML resistance during the chronic phase, our data clearly identified TWIST-1 as a downstream target of the BMP4/BMPR1b autocrine loop [
      • Grockowiak E.
      • Laperrousaz B.
      • Jeanpierre S.
      • et al.
      Immature CML cells implement a BMP autocrine loop to escape TKI treatment.
      ].This situation likely reflects evolution with time and upon treatment adaptation, in particular of the leukemic niche, as suggested in other cancers [
      • Duan C.W.
      • Shi J.
      • Chen J.
      • et al.
      Leukemia propagating cells rebuild an evolving niche in response to therapy.
      ]. It also argues that alteration of the BMP signaling pathway contributes to treatment survival of a subfraction of LSCs independently of the BCR-ABL oncogene because we showed that it remained efficiently targeted within these cells.
      While monitoring the evolution of the BMP pathway in a CML-resistant patient over almost a decade, we identified a progressive overproduction of the BMP4-soluble signal that dominated BMP2 in both LSCs and their altered bone marrow mesenchymal stem cells. This correlates with patient evolution toward the advanced transformed stage of CML [
      • Grockowiak E.
      • Laperrousaz B.
      • Jeanpierre S.
      • et al.
      Immature CML cells implement a BMP autocrine loop to escape TKI treatment.
      ]. Interestingly, BMP4 has been associated with the more aggressive AML [
      • Raymond A.
      • Liu B.
      • Liang H.
      • et al.
      A role for BMP-induced homeobox gene MIXL1 in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy.
      ]. Indeed, BMP4 has been involved in the induction of the MIXL1 gene upon binding to its type 1 receptor, BMPRI, and through the activation of SMAD signaling (SMAD5). The MIXL1 factor exerts an anti-apoptotic function that can participate in the drug resistance of AML cells. In addition, activation of BMP signaling has been demonstrated in pediatric acute megakaryoblastic leukemia, where the fusion protein CBFA2T3-GLIS2 is responsible for BMP2/BMP4 and ID1 overexpression and linked to an increase in self-renewal capacity for the hematopoietic progenitors [
      • Gruber T.A.
      • Larson Gedman A.
      • Zhang J.
      • et al.
      An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.
      ]. Conversely, in the context of acute promyelocytic leukemia, a type of AML with a high rate of complete remission in patients treated by all-trans retinoic acid, resistance to treatment can be observed in some patients. In this particular subtype of adult AML, the mechanism of resistance seems to involve BMP4/BMP6 gene expression that could control target genes involved in a differentiation block such as Id1 and Id2. Interestingly, this mechanism has been correlated with the PML/RARα fusion oncogene, which prevents differentiation of abnormal promyelocytes and induces resistance [
      • Topić I.
      • Ikić M.
      • Ivčević S.
      • et al.
      Bone morphogenetic proteins regulate differentiation of human promyelocytic leukemia cells.
      ]. Last, an important role of BMPs has been identified in MSCs of the leukemic niche to support AML cell growth [
      • Battula V.L.
      • Le P.M.
      • Sun J.C.
      • et al.
      AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth.
      ]. These combined data clearly point toward the BMP pathway as one of the major signaling pathways involved in all steps of myeloid malignancies.

      BMP pathway and lymphoid malignancies

      Various research groups have started to investigate the role of the BMP pathway in lymphoid leukemia. Using different patient cohorts, BMP2 overexpression has been identified in pre-B acute lymphoblastic leukemia (ALL) compared with CD34+ healthy cells, but not in T-cell ALL. This BMP2 overexpression was associated with alteration of other genes involved in the dialogue of immature leukemic cells with their bone marrow microenvironment [
      • Tesfai Y.
      • Ford J.
      • Carter K.W.
      • et al.
      Interactions between acute lymphoblastic leukemia and bone marrow stromal cells influence response to therapy.
      ]. In addition, overexpression of BMPR1a/BMPR1b and BMPR2 receptors was detected at the cell membrane of B-cell chronic lymphoid leukemia (CLL) leukemic cells. Moreover, disease progression seemed to be accompanied by a more pronounced overexpression of BMPR1a and BMPR1b, as measured in samples from patients in more advanced stages [
      • Dzietczenia J.
      • Wrobel T.
      • Jazwiec B.
      • Mazur G.
      • Butrym A.
      • Kuliczkowski K.
      Expression of cyclin A and bone morphogenetic protein receptors and response to induction therapy in patients with acute leukemias.
      ]. These findings suggest that overexpression of the receptor could favor the proliferative process. Finally, analysis of gene expression of the BMP signaling pathway in a cohort of 160 CLL patient samples showed alterations of SMAD1/8 that appeared overexpressed and correlated with a decrease in SMAD4 expression compared with control samples. High levels of SMAD1/8 transcripts expression were associated with poor prognosis [
      • Witkowska M.
      • Majchrzak A.
      • Cebula-Obrzut B.
      • Wawrzyniak E.
      • Robak T.
      • Smolewski P.
      The distribution and potential prognostic value of SMAD protein expression in chronic lymphocytic leukemia.
      ]. Interestingly, gene expression analysis of two independent datasets showed that the levels of inhibitory Smads varied across different B-cell lymphomas [
      • Huse K.
      • Bakkebo M.
      • Walchli S.
      • et al.
      Role of Smad proteins in resistance to BMP-induced growth inhibition in B-cell lymphoma.
      ]. In this context, the BMP pathway acts as a negative factor with exogenous BMPs, especially BMP7, that inhibit DNA synthesis of lymphoma cells. SMAD7 overexpression in cancer cells is sufficient to escape the negative effects of BMPs by inhibiting SMAD 1/5/8 signaling.
      The studies discussed here suggest that, in addition to the context of myeloid cells and solid tumors, alterations of the BMP signaling pathway may also be involved at different stages of the transformation process of lymphoid cells. However, these findings will require further investigation because they are still in their early stages.

      Conclusion: BMP pathway as a new therapeutic avenue

      The use of chemotherapy combined with inhibitory molecules against essential elements of the deregulated signaling pathways implicated in LSC regulation is emerging as a new and promising therapeutic choice. This could be applied to the BMP pathway in CML because we showed that BMPR1b overexpression is responsible for overexpansion of LSCs and resistance [
      • Grockowiak E.
      • Laperrousaz B.
      • Jeanpierre S.
      • et al.
      Immature CML cells implement a BMP autocrine loop to escape TKI treatment.
      ], suggesting the use of a combined conventional therapy with an effective BMPR1b inhibitory molecule. Depending on cancer type, BMP signaling needs to be either activated or inhibited. In several types of leukemia, BMP seems to be the key for better patient outcome [
      • Lowery J.W.
      • Brookshire B.
      • Rosen V.
      A survey of strategies to modulate the bone morphogenetic protein signaling pathway: current and future perspectives.
      ]. This inhibition of the pathway can be achieved, for instance, by trapping the extracellular BMP ligands from the microenvironment using antagonist molecules such as Noggin, Chordin, or Gremlin to prevent ligand–receptor interaction. For example, inhibitors of type I BMP receptor such as Dorsomorphin or LDN-193189 molecules avoid the binding of the ligand to its receptor [
      • Lowery J.W.
      • Brookshire B.
      • Rosen V.
      A survey of strategies to modulate the bone morphogenetic protein signaling pathway: current and future perspectives.
      ]. The use of several inhibitory molecules against BMP type I receptors has indeed been initiated in the context of adult AML using LDN-193189 to restore chemotherapy sensitivity [
      • Raymond A.
      • Liu B.
      • Liang H.
      • et al.
      A role for BMP-induced homeobox gene MIXL1 in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy.
      ]. Targeting the intrinsic and extrinsic elements of the BMP pathway for novel therapeutic approaches promises to be an important tool for effective long-term cancer SC eradication according to our recent findings and to the recurrent alterations of this pathway in hematological malignancies and solid tumors [
      • Zhang L.
      • Ye Y.
      • Long X.
      • Xiao P.
      • Ren X.
      • Yu J.
      BMP signaling and its paradoxical effects in tumorigenesis and dissemination.
      ,
      • Lowery J.W.
      • Brookshire B.
      • Rosen V.
      A survey of strategies to modulate the bone morphogenetic protein signaling pathway: current and future perspectives.
      ,
      • Hopkins C.R.
      Inhibitors of the bone morphogenetic protein (BMP) signaling pathway: a patent review (2008–2015).
      ]. However, elucidating the functional importance of BMP receptor localization within different cellular compartments remains a major unresolved issue. Therefore, the development of more specific antagonist or inhibitory molecules will be necessary to target the relevant element without affecting other ligands and to preserve the normal function of this very pleiotropic and fundamental signaling pathway. Nevertheless, modulation of the BMP signaling pathway is a different and unique way to develop innovative patient treatments that could simultaneously take into account the important involvement of this pathway in the dynamic evolution of the tumor ecosystem.

      Conflict of interest statement

      The authors declare no competing financial interests.

      Acknowledgments

      The authors acknowledge Barbara White-Meunier, Ph.D., for proofreading the manuscript.
      This work was supported by grants to F-EN and/or VM-S from the Patients' Association LMC France and its president, Mina Daban, Fondation de France ( 2014-0047501 ); Association Laurette Fugain ( ALF2014-03 ); Ligue Contre le Cancer (Haute Savoie, Loire, Puy de Dôme and Rhone); and Région Rhône-Alpes Auvergne ( C-MIRA14.007020 ). A doctoral fellowship was obtained from Mexican Conacyt government (MFV) and from Fondation ARC (FZ).

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