The driver role of JAK‐STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy‐ and castration‐resistant prostate cancer

Abstract

Background Lineage plasticity in prostate cancer (PCa) has emerged as an important mechanism leading to the onset of therapy‐ and castration‐resistant PCa (t‐CRPC), which is closely associated with cancer stem cell (CSC) activity. This study is to identify critical driver(s) with mechanism of action and explore new targeting strategy. Methods Various PCa cell lines with different genetic manipulations were subjected to in vitro prostasphere assay, cell viability assay and in vivo stemness potential. In addition, bioinformatic analyses such as Ingenuity pathway and Gene Set Enrichment Analysis were carried out to determine clinical relevance. The in vivo anti‐tumour activity of JAK or STAT1 inhibitors was examined in clinically relevant t‐CRPC model. Results We demonstrated the role of interferon‐related signalling pathway in promoting PCa stemness, which correlated with significant elevation of interferon related DNA damage resistance signature genes in metastatic PCa. Inhibition of JAK‐STAT1 signalling suppresses the in vitro and in vivo CSC capabilities. Mechanistically, IFIT5, a unique downstream effector of JAK‐STAT1 pathway, can facilitate the acquisition of stemness properties in PCa by accelerating the turnover of specific microRNAs (such as miR‐128 and ‐101) that can target several CSC genes (such as BMI1, NANOG, and SOX2). Consistently, knocking down IFIT5 in t‐CRPC cell can significantly reduce in vitro prostasphere formation as well as decrease in vivo tumour initiating capability. Conclusions This study provides a critical role of STAT1‐IFIT5 in the acquisition of PCSC and highlights clinical translation of JAK or STAT1 inhibitors to prevent the outgrowth of t‐CRPC.

Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells

“…On the other hand, inhibitors of WNT/b-catenin (XAV-939), AKT (Capiversatib), HDAC (Panobinostat) and proteosome/NFkB (Bortezomib) all demonstrated an inhibitory effect or trend on prostate regeneration (Figure 6J), implicating these pathways in driving L1 generation and L1 regenerative activities. We also find JAK/STAT, which has received a lot of attention recently in relation to advanced PCa lineage plasticity [78][79][80] , to be one of the pathways deregulated in L1; however, we do not see any deregulation or enrichment of Stat motifs with castration in our scATAC studies. Furthermore, STAT chromatin recruitment has not been demonstrated in any of the recent studies, leaving us to wonder how JAK/STAT may be regulating treatment-induced plasticity.…”

The Role of JAK-STAT-SOCS1 Axis in Tumorigenesis, Malignant Progression and Lymphatic Metastasis of Penile Cancer

“…In term of metastases, Wang et al found that JAK2 and STAT3 can contribute to cancer cell proliferation and migration in colorectal cancer 28 . In term of treatment, JAK-STAT inflammatory signaling was enhanced in prostate cancer tumor cells which can lead to drug resistance 13 , 29 . JAK-STAT axis is a core signaling axis in a wide variety of t cancer 30 .…”

ZNF397 Loss Triggers TET2-driven Epigenetic Rewiring, Lineage Plasticity, and AR-targeted Therapy Resistance in AR-dependent Cancers

“…On one hand, TET2 and TET2-dependent 5hmC oxidation is known to offset the transcriptional signaling driven by AR, which impairs the progression of primary PCa and is correlated with better clinical outcomes 34 .On the other hand, TET2-medaited 5hmC transition is highly enriched in the establishment of stem-like and neuronal lineages during development and carcinogenesis of various cancers 43,44 and, consequently, associated with poor clinical outcomes. Interestingly, TET2 was also implicated in the induction of cytokine signaling in T-cell-mediated immune responses 50 , which was known to regulate PCa lineage plasticity 17,18,64 . Contrary to the conventional view of its tumor suppressor role in primary PCa, our findings revealed that TET2-driven epigenetic reprogramming is a powerful mechanism that promotes the transition of mCRPC cancer cells from an AR-driven luminal lineage to a TET2-driven lineage plastic state expressing EMT-like, stem-like and NE-like lineages, which then fail to respond to AR-targeted therapy.…”