Transcriptional Inactivation of TP53 and the BMP Pathway Mediates Therapy-induced Dedifferentiation and Metastasis in Prostate Cancer

Abstract

Unsupervised clustering and deconvolution analysis identifies a novel subtype of M-CRPC endowed with hybrid epithelial/mesenchymal (E/M) and luminal progenitor-like traits (Mesenchymal and Stem-like PC, MSPC). Analysis of patient datasets and mechanistic studies indicate that MSPC arises as a consequence of therapy-induced lineage plasticity. AR blockade instigates two separate and complementary processes: 1) transcriptional silencing of TP53 and hence acquisition of hybrid E/M and stem-like traits; and 2) inhibition of the BMP signaling, which promotes resistance to the pro-apoptotic and anti-proliferative effects of AR inhibition. The drug-tolerant prostate cancer cells generated through reprogramming are rescued by neuregulin and generate metastases in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibit efficacy in preclinical models of mixed ARPC/MSPC or MSPC, respectively. These results identify a novel subtype of M-CRPC, trace its origin to therapy-induced lineage plasticity, and reveal its dependency on HER2/3 signaling.

Metabolic fingerprinting of chemotherapy-resistant prostate cancer stem cells. An untargeted metabolomic approach by liquid chromatography-mass spectrometry

“…Interestingly, those SCL tumors were negative or had low expression of the AR (Tang et al, 2022). In another study, Han et al identified a stem-like PCa subtype of metastatic castration-resistant prostate cancer that arose from ARpositive cells as a consequence of its blockade with enzalutamide and therapy-induced lineage plasticity (Han et al, 2022). In this study, we have used a prostate cancer cell line adapted to grow in the presence of the antiandrogen 2-hydroxyflutamide, that displays characteristics of stem cells like an enhanced expression of the pump that efflux Frontiers in Cell and Developmental Biology frontiersin.org 13 accumulated drugs inside the cell, ABCB1A, increased expression of the pluripotency factors Nanog and the Yamanaka factor Oct4, as well as low levels of the AR.…”

NSD2 maintains lineage plasticity and castration-resistance in neuroendocrine prostate cancer

“…1e,f; Extended Data Fig. 2b), thereby resembling human CRPC-adeno and also "mesenchymal stem-like prostate cancer" (MSPC) 43 . Cluster 2 lacked activity of AR and displayed low-moderate activity of most NE markers, whereas Cluster 3 resembled CRPC-NE, with high activity of CHGA, ASCL1, and FOXA2; interestingly, a subpopulation of Cluster 3 displayed AR activity, potentially corresponding to AMPC.…”