Tgfbr2 inactivation facilitates cellular plasticity and development of Pten-null prostate cancer

Abstract

Mutations in tumors can create a state of increased cellular plasticity that promotes resistance to treatment. Thus, there is an urgent need to develop novel strategies for identifying key factors that regulate cellular plasticity in order to combat resistance to chemotherapy and radiation treatment. Here we report that prostate epithelial cell reprogramming could be exploited to identify key factors required for promoting prostate cancer tumorigenesis and cellular plasticity. Deletion of phosphatase and tensin homolog (Pten) and transforming growth factor-beta receptor type 2 (Tgfbr2) may increase prostate epithelial cell reprogramming efficiency in vitro and cause rapid tumor development and early mortality in vivo. Tgfbr2 ablation abolished TGF-β signaling but increased the bone morphogenetic protein (BMP) signaling pathway through the negative regulator Tmeff1. Furthermore, increased BMP signaling promotes expression of the tumor marker genes ID1, Oct4, Nanog, and Sox2; ID1/STAT3/NANOG expression was inversely correlated with patient survival. Thus, our findings provide information about the molecular mechanisms by which BMP signaling pathways render stemness capacity to prostate tumor cells.

Regulation of stem/progenitor cell maintenance by BMP5 in prostate homeostasis and cancer initiation

“…To validate whether the increase in BMP signaling was involved in Pten -deficient tumors, we treated Pten -deficient prostate organoids and mouse prostate tumors with a selective inhibitor against BMP signaling, which resulted in blunted organoid passaging potential and a delay in tumor progression in vivo. These results are in line with a previous report showing that loss of TGFβ signaling has been linked to prostate cancer progression in Pten -deficient tumor, in part through upregulation of BMP signaling ( Zhao et al, 2018 ). Here, we identify the ligand BMP5 as prime driver of Pten -deficient cancer progression.…”

“…In contrast, basal stem cells are constitutively multipotent in the developing prostate, where they populate the luminal cell layer through asymmetric cell divisions ( Ousset et al, 2012 ; Shafer et al, 2017 ; Wang et al, 2014a ). In prostate cancer, basal and luminal stem cells can both act as tumor-initiating cells and are thought to contribute to tumor recurrence ( Choi et al, 2012 ; Goldstein et al, 2010 ; Wang et al, 2009 ; Wang et al, 2013 ; Zhao et al, 2018 ).…”

TMEFF1 overexpression and its mechanism for tumor promotion in ovarian cancer

“…Gery et al showed that TMEFF1 expression in brain tumor tissue exhibited a significantly low level compared to normal brain tissues, and tumor cell lines with low TMEFF1 expression are more likely to show a strong proliferative capacity and a malignant profile 6. Similar results were also validated in colon cancer and prostate cancer,8,15 indicating that TMEFF1 plays a role as an anticarcinogenic gene in these tumors. However, the role of TMEFF1 in ovarian cancer has not yet been elucidated.…”

“…Harms and Chang found that, by binding with the co-receptor, Cripto-1, TMEFF1 interrupted the binding of Cripto-1 to the ALK4 receptor and, thus, inhibited the effects of nodal signals, further mediating the TGF-β signaling pathway to regulate the growth of cells and tissues 13,16. In a recent study, a deficiency of TGF-βR2 in prostate cancer negatively regulated TMEFF1 and thus activated the BMP signaling pathway to influence the prognosis of patients 15. Here, we discovered, for the first time, that TMEFF1 participated in the malignant biological behavior of ovarian cancer by activating the MAPK pathways and the PI3K/AKT pathway.…”

Opposing roles and potential antagonistic mechanism between TGF-β and BMP pathways: Implications for cancer progression

“…Tmeff1 is also proven to be a direct target of TGF-β2/Smad2/3 signalling in hair follicle stem cell; as a result, TGF-β signalling counterbalances BMP-mediated effects by upregulating the expression of Tmeff1 [56]. Moreover, a study in prostate cancer shows that Tmeff1, which is induced by TGF-β signalling, also causes Smad1 and Smad5 to degrade through its interaction with Smurf1, thus inhibiting the BMP signalling pathway [57].…”