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Prostate cancer (PCa) lethality is driven by its progression to a metastatic castration-resistant state, yet the signaling mechanisms underlying metastatic spread remain unknown. Here we show that STAT3 converges with the LKB1/mTORC1 and CREB to control metastatic disease in PCa mouse models. Unexpectedly, STAT3 was found to be upregulated in diabetic PCa patients undergoing metformin therapy with a concomitant reduction in mTORC1 expression. In preclinical mouse models of PCa, genetic ablation or activation of STAT3 had opposing effects on LKB1/AMPK/mTORC1- dependent tumorigenesis. Using genetic and pharmacological approaches, we identified LKB1 as a direct STAT3 target while repressing CREB. Furthermore, PCa patients with high CREB expression had inferior clinical outcome with significantly increased risk of disease and metastatic recurrence. We observe that castration state lowers STAT3 abundance and increases AR and CREB levels, leading to castration-resistant PCa (CRPC). Our findings revealed that STAT3 controls mTORC1 and CREB in metastatic disease, suggesting CREB as a promising target for lethal CRPC.

Cancer progression is characterized and driven by gradual loss of a differentiated phenotype and gain of stem cell-like features. In prostate cancer (PCa), androgen receptor (AR) signaling is important for cancer growth, progression, and emergence of therapy resistance. Targeting the AR signaling axis has been, over the decades, the mainstay of PCa therapy. However, AR signaling at the transcription level is reduced in high-grade cancer relative to low-grade PCa and loss of AR expression promotes a stem cell-like phenotype, suggesting that emergence of resistance to AR-targeted therapy may be associated with loss of AR signaling and gain of stemness. In the present mini-review, we first discuss PCa from the perspective of an abnormal organ with increasingly deregulated differentiation, and discuss the role of AR signaling during PCa progression. We then focus on the relationship between prostate cancer stem cells (PCSCs) and AR signaling. We further elaborate on the current methods of using transcriptome-based stemness-enriched signature to evaluate the degree of oncogenic dedifferentiation (cancer stemness) in pan-cancer datasets, and present the clinical significance of scoring transcriptome-based stemness across the spectrum of PCa development. Our discussions highlight the importance to evaluate the dynamic changes in both stem cell-like features (stemness score) and AR signaling activity across the PCa spectrum.

Prostate cancer (PCa) is heterogeneous and typically presents with multiple distinct cancer foci. Androgen receptor signaling inhibitors (ARSIs) are standard-of-care therapies for advanced PCa and can prolong patient survival by months. Treatment-naïve PCa harbors a population of stem-like cells (AR-/lo) functionally defined as PCa stem cells (PCSCs). During cancer progression or upon therapeutic treatment, non-CSCs may undergo cellular plasticity and be reprogrammed to PCSCs. As a result, PCSCs may become the predominant cell population in advanced (Gleason 9/10) and ARSI-resistant tumors, and the “root cause” for drug resistance. However, current ARSI-based treatment regimens primarily target AR+ CRPC cells or clones but largely ignore AR-/lo cells. microRNA-34a (miR-34a), a tumor-suppressive miRNA dysregulated in PCa, is a potent PCSC inhibitor by targeting cellular processes essential for CSC survival and functions. Here we aim to develop novel miR-34a therapeutics to target PCa cell heterogeneity and CRPC. miR-34a expression negatively correlates with the tumor stage in PCa samples. And miR-34a expression is significantly reduced in p53 mutated tumors. We explored two novel miR-34a delivery platforms. The first is packaging-free ligand-mediated conjugate utilizing 2- [3-(1,3-dicarboxy propyl) ureido] pentanedioic acid (DUPA) as a high-affinity binding ligand for prostate-specific membrane antigen (PSMA), which is upregulated in PCa. The second platform uses cationic lipid nanoparticles to package miR-34a (LNP-miR-34a). We show that during PCa progression and upon treatment, PSMA expression is upregulated and continues to be highly expressed in CRPC and PSMA expression level negatively correlates with overall survival in PCa. Moreover, DUPA-conjugate can specifically target PSMA-expressing PCa both in vitro and in vivo. DUPA-miR-34a significantly induces target gene silencing in vitro. On the other hand, LNP show good encapsulation efficiency for miR-34a, LNP-miR-34a significantly repressed cell proliferation by downregulating critical stemness factors in a dose-dependent manner. Meanwhile, we are pursuing chemical modifications of the miR-34a mimics aiming to improve serum stability and future in vivo applications. Both fully modified miR-34a (FM-miR-34a) and partially-modified-miR-34a (PM-miR-34a) exhibit improved serum stability without compromising the functionality. Our data suggest that DUPA-miR-34a represents a promising novel therapeutic for PCSC-enriched CRPC that continue to express PSMA, whereas LNP-miR-34a could be a systemic therapeutic for CRPC treatment in the combinatorial setting. miR-34a, as a direct target and a major mediator of p53 functions, may represent an effective replacement therapeutic in p53-mutated advanced PCa. Citation Format: Wen (Jess) Li, Xiaozhuo Liu, Ahmed M. Abdelaal, Sudarsan Kasireddy, Yafei Su, Yun Wu, Andrea L. Kasinski, Dean G. Tang. Further development of microRNA-34a therapeutics to target castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2716.

Prostate cancer (PCa) is a highly heterogeneous disease and typically presents with multiple distinct cancer foci. Heterogeneity in androgen receptor (AR) expression levels in PCa has been observed for decades, from untreated tumors to castration-resistant prostate cancer (CRPC) to disseminated metastases. Current standard-of-care therapies for metastatic CRPC can only extend life by a few months. Cancer stem cells (CSCs) are defined as a subpopulation of cancer cells that exists in almost all treatment-naive tumors. Additionally, non-CSCs may undergo cellular plasticity to be reprogrammed to prostate cancer stem cells (PCSCs) during spontaneous tumor progression or upon therapeutic treatments. Consequently, PCSCs may become the predominant population in treatment-resistant tumors, and the “root cause” for drug resistance. microRNA-34a (miR-34a) is a bona fide tumor-suppressive miRNA, and its expression is dysregulated in PCa. Importantly, miR-34a functions as a potent CSC suppressor by targeting many molecules essential for CSC survival and functions, which makes it a promising anti-PCSC therapeutic. Here, we conducted a comprehensive literature survey of miR-34a in the context of PCa and especially PCSCs. We provided an updated overview on the mechanisms of miR-34a regulation followed by discussing its tumor suppressive functions in PCa. Finally, based on current advances in miR-34a preclinical studies in PCa, we offered potential delivery strategies for miR-34a-based therapeutics for treating advanced PCa.