Altered BMP2/4 Signaling in Stem Cells and Their Niche: Different Cancers but Similar Mechanisms, the Example of Myeloid Leukemia and Breast Cancer

Abstract

Understanding mechanisms of cancer development is mandatory for disease prevention and management. In healthy tissue, the microenvironment or niche governs stem cell fate by regulating the availability of soluble molecules, cell-cell contacts, cell-matrix interactions, and physical constraints. Gaining insight into the biology of the stem cell microenvironment is of utmost importance, since it plays a role at all stages of tumorigenesis, from (stem) cell transformation to tumor escape. In this context, BMPs (Bone Morphogenetic Proteins), are key mediators of stem cell regulation in both embryonic and adult organs such as hematopoietic, neural and epithelial tissues. BMPs directly regulate the niche and stem cells residing within. Among them, BMP2 and BMP4 emerged as master regulators of normal and tumorigenic processes. Recently, a number of studies unraveled important mechanisms that sustain cell transformation related to dysregulations of the BMP pathway in stem cells and their niche (including exposure to pollutants such as bisphenols). Furthermore, a direct link between BMP2/BMP4 binding to BMP type 1 receptors and the emergence and expansion of cancer stem cells was unveiled. In addition, a chronic exposure of normal stem cells to abnormal BMP signals contributes to the emergence of cancer stem cells, or to disease progression independently of the initial transforming event. In this review, we will illustrate how the regulation of stem cells and their microenvironment becomes dysfunctional in cancer via the hijacking of BMP signaling with main examples in myeloid leukemia and breast cancers.

Keywords: BMP; bisphenol; cancer; environmental exposure; mesenchymal; microenvironment; resistance; stem cells.

FIGURE 1

Alterations of the BMP pathway involved in early steps of transformation. (1a) Decrease in ligand (BMP2 and/or BMP4) and increase in type1 BMP-receptor at time of diagnosis in stem cells of diferent leukemia and breast cancer types. (1b) Increase in ligand (BMP2 and/or BMP4) production by stromal cells of the tumor microenvironement at time of diagnosis in diferent leukemia and breast cancer types. (2) Cooperation between BMP2 overproduction by the stroma and IL6 to induce BMPR1b overexpressing stem-cells transformation. (3) BMP4 mediated reprogrammation of mature cells toward an imature stem-like cell. (4) Effect of environmental polluant on the expression of both ligand and BMPR1 expression in healthy cells.

FIGURE 2

Alterations of the BMP pathway upon treatment of CML cancer stem cells. (1) Setting of a BMP4 autocrine loop in CSCs that controls Twist1 expression to promote resistance of CML CSCs to tyrosine kinase inhibitors (TKIs) and retained high production of BMP4 by bone marrow mesenchymal stromal cells of resistant patients. (2) At patients remission under TKI treatment, CSCs showed a co-enrichment in BMP and Jak2-signaling, quiescence and SC signatures, as identified by single cell RNA-Seq analysis of TKI-persisting cells. In persisting CSCs, BMPR1b-cells displayed co-activated Smad1/5/8 and Stat3 pathways that are targeted by blocking BMPR1B/Jak2 signal using, for example, a specific BMPR1b inhibitor (E6201) or Jak2 (AG490) inhibitor. The TKI-induced quiescence of residual CSCs relies on a BMP4 signal delivered by surrounding mesenchymal cells and inhibited by the BMPR1B inhibitor (E6201). Dual targeting of BMP and Jak2 efficiently reverses TKI-dependent induction of quiescence and allowed re-entry into a differentiation process of the BMPR1b⁺ CSC sub-fraction that was adherent to the stroma.