Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming

Abstract

Prostate cancer is an androgen-dependent disease subject to interactions between the tumor epithelium and its microenvironment. Here, we found that epigenetic changes in prostatic cancer-associated fibroblasts (CAF) initiated a cascade of stromal-epithelial interactions. This facilitated lethal prostate cancer growth and development of resistance to androgen signaling deprivation therapy (ADT). We identified a Ras inhibitor, RASAL3, as epigenetically silenced in human prostatic CAF, leading to oncogenic Ras activity driving macropinocytosis-mediated glutamine synthesis. Interestingly, ADT further promoted RASAL3 epigenetic silencing and glutamine secretion by prostatic fibroblasts. In an orthotopic xenograft model, subsequent inhibition of macropinocytosis and glutamine transport resulted in antitumor effects. Stromal glutamine served as a source of energy through anaplerosis and as a mediator of neuroendocrine differentiation for prostate adenocarcinoma. Antagonizing the uptake of glutamine restored sensitivity to ADT in a castration-resistant xenograft model. In validating these findings, we found that prostate cancer patients on ADT with therapeutic resistance had elevated blood glutamine levels compared with those with therapeutically responsive disease (odds ratio = 7.451, P = 0.02). Identification of epigenetic regulation of Ras activity in prostatic CAF revealed RASAL3 as a sensor for metabolic and neuroendocrine reprogramming in prostate cancer patients failing ADT.

GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer

“…However, alternative pathway(s) outside of AR signaling are also associated with prostate cancer. Recently, various signaling pathways, such as growth factors, cytokines, miRNA and epigenetic control, were reported to be related to progression of prostate cancer and conversion into CRPC, indicating that these signaling pathways could be novel therapeutic targets . Among these alternate pathways, in our study, we focused on orphan GPCRs.…”

“…Recently, various signaling pathways, such as growth factors, cytokines, miRNA and epigenetic control, were reported to be related to progression of prostate cancer and conversion into CRPC, indicating that these signaling pathways could be novel therapeutic targets. 3,34,35 Among these alternate pathways, in our study, we focused on orphan GPCRs. Integrative analyses of gene expression profiles of prostate cancer cell lines indicated that expression levels of the orphan GPCR, GPRC5A, are significantly related to overall survival of prostate cancer patients, suggesting that GPRC5A can be a candidate therapeutic target molecule involved in prostate cancer progression (Fig.…”

Epigenetic modulations and lineage plasticity in advanced prostate cancer

“…It has been long known that cancer-associate fibroblasts can promote the progression and/or initiation of prostate epithelial cells via regulating extracellular matrix and growth factors. 97 Mishra et al 98 also reported that epigenetic changes in prostatic cancer-associated fibroblasts initiate stromaleepithelial interactions. This interaction facilitated tumor growth and development of resistance to ADT.…”

Nutritional Exchanges Within Tumor Microenvironment: Impact for Cancer Aggressiveness

“…Intriguingly, although lactate is the most abundant nutrient provided in the TME, CAFs are also able to supply amino acids like glutamine to cancer cells. Epithelial cancer cells incorporate fibroblasts-derived glutamine replenishing their TCA cycle, as well as promoting an increase in aspartate-mediated nucleotide anabolism, the accumulation of oxidized glutathione and the activation of protein synthesis (85). Glutamine dependency as it is exploited as a carbon source for the energetic purposes and as a nitrogen source for nucleotide biosynthesis reflects the fact such amino acid is the most commonly depleted amino acid in TME (33).…”