BMP et cancer

Sagorny, Karen; Chapellier, Marion; Laperrousaz, Bastien; Maguer-Satta, Véronique

doi:10.1051/medsci/2012284020

Cited by 10 publications

(7 citation statements)

References 33 publications

(31 reference statements)

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“…Several lines of evidence support a role for BMP signaling in stem cell regulation where it maintains the proliferative potential of adult stem cells (27). Recent reports demonstrate an interaction between TP63 and BMP signaling.…”

Section: Resultsmentioning

confidence: 99%

ΔNp63α-Mediated Activation of Bone Morphogenetic Protein Signaling Governs Stem Cell Activity and Plasticity in Normal and Malignant Mammary Epithelial Cells

Balboni

Hutchinson

DeCastro³

et al. 2013

Cancer Research

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Genetic analysis of TP63indicates that ΔNp63 isoforms are required for preservation of regenerative stasis within diverse epithelial tissues. In squamous carcinomas, TP63 is commonly amplified, and ΔNp63α confers a potent survival advantage. Genome-wide occupancy studies demonstrate that ΔNp63 promotes bidirectional target gene regulation by binding >5000 sites throughout the genome; however, the subset of targets mediating discreet activities of TP63 remains unclear. We report that ΔNp63α activates BMP signaling by inducing the expression of BMP7. Immunohistochemical analysis indicates that hyper-activation of BMP signaling is common in human breast cancers, most notably in the basal molecular subtype, as well as in several mouse models of breast cancer. Suppression of BMP signaling in vitro with LDN193189, a small molecule inhibitor of BMP Type I Receptor kinases, represses clonogenicity and diminishes the cancer stem cell enriched ALDH1+ population. Importantly, LDN193189 blocks reconstitution of mixed ALDH1+/ALDH1- cultures indicating that BMP signaling may govern aspects of cellular plasticity within tumor hierarchies. These results show that BMP signaling enables reversion of committed populations to a stem-like state, potentially supporting progression and maintenance of tumorigenesis. Treatment of a mouse model of breast cancer with LDN193189 caused reduced expression of markers associated with epithelial to mesenchymal transition (EMT). Furthermore, in vivo limiting dilution analysis assays revealed that LDN193189 treatment suppressed tumor-initiating capacity and increased tumor latency. These studies support a model in which ΔNp63α-mediated activation of BMP signaling governs epithelial cell plasticity, EMT, and tumorigenicity during breast cancer initiation and progression.

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Section: Resultsmentioning

confidence: 99%

ΔNp63α-Mediated Activation of Bone Morphogenetic Protein Signaling Governs Stem Cell Activity and Plasticity in Normal and Malignant Mammary Epithelial Cells

Balboni

Hutchinson

DeCastro³

et al. 2013

Cancer Research

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“…According to the context, BMPs could participate in initial tumor suppression or favor CSC maintenance and metastasis 8 . Within the BMP family, BMP2 and BMP4 have emerged as key regulators of normal and cancer SCs 11 – 13 . We have previously demonstrated that alterations in the BMP pathway at intrinsic (BMP receptors and downstream partners) and extrinsic (BMP extracellular ligands) levels constitute major events in transformation, expansion and persistence of immature cells in chronic phase chronic myeloid leukemia (CML) and breast cancer, by diverting their normal functions 11 , 12 , 14 , 15 .…”

Section: Introductionmentioning

confidence: 99%

A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome

Voeltzel¹,

Flores-Violante²,

Zylbersztejn³

et al. 2018

Cell Death Dis

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In a significant number of cases cancer therapy is followed by a resurgence of more aggressive tumors derived from immature cells. One example is acute myeloid leukemia (AML), where an accumulation of immature cells is responsible for relapse following treatment. We previously demonstrated in chronic myeloid leukemia that the bone morphogenetic proteins (BMP) pathway is involved in stem cell fate and contributes to transformation, expansion, and persistence of leukemic stem cells. Here, we have identified intrinsic and extrinsic dysregulations of the BMP pathway in AML patients at diagnosis. BMP2 and BMP4 protein concentrations are elevated within patients’ bone marrow with a BMP4-dominant availability. This overproduction likely depends on the bone marrow microenvironment, since MNCs do not overexpress BMP4 transcripts. Intrinsically, the receptor BMPR1A transcript is increased in leukemic samples with more cells presenting this receptor at the membrane. This high expression of BMPR1A is further increased upon BMP4 exposure, specifically in AML cells. Downstream analysis demonstrated that BMP4 controls the expression of the survival factor ΔNp73 through its binding to BMPR1A. At the functional level, this results in the direct induction of NANOG expression and an increase of stem-like features in leukemic cells, as shown by ALDH and functional assays. In addition, we identified for the first time a strong correlation between ΔNp73, BMPR1A and NANOG expression with patient outcome. These results highlight a new signaling cascade initiated by tumor environment alterations leading to stem-cell features and poor patients’ outcome.

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“…BMP signaling affects the stem cell niche both directly and indirectly ( Zhang et al., 2003 ). Within this family, BMP2 and BMP4 are important regulators of both normal and cancer stem cells ( Laperrousaz et al., 2013; Sagorny et al., 2012 ). In breast cancer, BMP2 and BMP4 have both protumor and antitumor functions ( Balboni et al., 2013; Clement et al., 2005 ), but alterations of BMP receptors and their intracellular signal transducers SMAD1/5/8 clearly contribute to cancer progression and metastasis ( Helms et al., 2005; Katsuno et al., 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Disequilibrium of BMP2 Levels in the Breast Stem Cell Niche Launches Epithelial Transformation by Overamplifying BMPR1B Cell Response

et al. 2015

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SummaryUnderstanding the mechanisms of cancer initiation will help to prevent and manage the disease. At present, the role of the breast microenvironment in transformation remains unknown. As BMP2 and BMP4 are important regulators of stem cells and their niches in many tissues, we investigated their function in early phases of breast cancer. BMP2 production by tumor microenvironment appeared to be specifically upregulated in luminal tumors. Chronic exposure of immature human mammary epithelial cells to high BMP2 levels initiated transformation toward a luminal tumor-like phenotype, mediated by the receptor BMPR1B. Under physiological conditions, BMP2 controlled the maintenance and differentiation of early luminal progenitors, while BMP4 acted on stem cells/myoepithelial progenitors. Our data also suggest that microenvironment-induced overexpression of BMP2 may result from carcinogenic exposure. We reveal a role for BMP2 and the breast microenvironment in the initiation of stem cell transformation, thus providing insight into the etiology of luminal breast cancer.

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BMP et cancer

Cited by 10 publications

References 33 publications

ΔNp63α-Mediated Activation of Bone Morphogenetic Protein Signaling Governs Stem Cell Activity and Plasticity in Normal and Malignant Mammary Epithelial Cells

ΔNp63α-Mediated Activation of Bone Morphogenetic Protein Signaling Governs Stem Cell Activity and Plasticity in Normal and Malignant Mammary Epithelial Cells

A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome

Disequilibrium of BMP2 Levels in the Breast Stem Cell Niche Launches Epithelial Transformation by Overamplifying BMPR1B Cell Response

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