Despite considerable progress in elucidating mechanisms leading to castration-resistant prostate cancer (CRPC), insight into the early stages of prostate cancer initiation and progression remains limited. Genomic drivers of prostate cancer initiation have been defined through patient tumor sequencing, but the subsequent events responsible for local tissue invasion are poorly understood. Here we leverage a well-studied genetically engineered mouse prostate cancer model (Hi-Myc) that, based on robust and reproducible kinetics for transitioning from pre-invasive prostatic intraepithelial neoplasia (PIN) to invasive prostate adenocarcinoma (PCa), provides an ideal system to systematically address this question using single-cell analysis. Surprisingly, the transcriptomic profiles of early PIN lesions are indistinguishable from those of late-stage, highly invasive tumor cells, suggesting that MYC activation at the PIN stage establishes a transcriptional program that is fully capable of driving invasion but is restrained by the local tumor microenvironment (TME). Indeed, we find that progression to PCa is associated with progressive infiltration of IL-1β+ tumor-infiltrating macrophages at the PIN stage that, based on immunodepletion and cytokine neutralization experiments, are required for the PIN-to-PCa transition. Mechanistically, IL-1β from macrophages acts directly on prostate fibroblasts, leading to the release of IL-6, which drives invasion by activating IL-6R in tumor cells. Collectively, these findings identify a pro-tumorigenic IL-1β/IL-6 signaling circuit mediated through local macrophages and fibroblasts that unleashes the full oncogenic potential of a cancer driver (MYC) activated at the PIN stage. We also find evidence of this circuit in other (non-MYC-driven) prostate cancer models as well as human prostate and lung adenocarcinoma, with implications for TME-specific targeted therapeutics in early-stage disease.
It is demonstrated that INSM1 is consistently upregulated across NEPC patient tumors and experimental models, including both ASCL1⁺ and NEUROD1⁺ molecular subtypes, as revealed by integrated bulk and single-cell transcriptomic analyses.
Chiachen Chen, Siyuan Cheng, Lin Li et al.· bioRxiv· 0 citations
Rational combination strategies are outlined that simultaneously target the RAS/MAPK axis and key TME vulnerabilities, such as immunotherapy combinations, CAF reprogramming, and ECM normalization, to overcome stromal-mediated resistance and achieve deeper, more sustained clinical responses.
Wen-Hao Ma, Xing-Yu Guo, Xiu-Ting Liu· Cancer Advances· 0 citations
Prostate adenocarcinoma remains one of the most commonly diagnosed malignancies in men, and advanced disease continues to present major therapeutic challenges. The androgen receptor (AR) is the principal driver of prostate cancer progression, and inhibition of AR signaling remains the standard treatment for metastatic disease. However, many patients progress to metastatic castration-resistant prostate cancer (CRPC), a lethal stage characterized by heterogeneous tumor cell populations with distinct AR expression and activity states. We previously identified an inverse relationship between AR signaling and expression of interleukin-1[beta] (IL-1[beta]), a pro-inflammatory cytokine that promotes skeletal colonization and progression of prostate cancer cells. This dissertation investigated the molecular mechanisms governing IL-1[beta] regulation in prostate cancer and the role of tumor-derived IL-1[beta] in AR-heterogeneous tumors. We demonstrated that patients with low AR activity and high IL-1[beta] expression exhibit significantly worse overall survival than patients with high AR activity and low IL-1[beta] expression. Mechanistically, we found that AR splice variants, including AR-45 and AR-V7, repress IL-1[beta] transcription similarly to full-length AR. We further identified constitutive JAK2/STAT1 signaling as the pathway driving IL-1[beta] transcription specifically in AR-negative prostate cancer cells, while cathepsin B mediated IL-1[beta] maturation independently of canonical inflammasome activation and caspase-1 activity. Finally, we demonstrated that tumor-derived IL-1[beta] suppresses AR signaling and induces IL-1[beta] expression in neighboring AR-positive cells through paracrine signaling. Collectively, these findings establish a mechanistic framework linking AR signaling, JAK2/STAT1 activation, cathepsin B-dependent IL-1[beta] processing, and paracrine cytokine signaling in metastatic CRPC while identifying IL-1[beta] signaling as a potential therapeutic target in advanced prostate cancer.
Prostate cancer is one of the most common cancers and a leading cause of cancer death in men. Tumor cell plasticity is a key driver of prostate cancer progression, metastasis, and resistance to androgen receptor pathway inhibitors (ARPIs), yet no approved therapies directly target this process. ESE3/EHF (EHF) is an epithelial-specific ETS transcription factor highly expressed in normal prostate epithelium and frequently downregulated in aggressive primary tumors, castration-resistant (CRPC) and neuroendocrine (NEPC) prostate cancers. Reduced EHF expression is associated with attenuated androgen receptor (AR) signaling, lineage plasticity and treatment resistance. In human cell lines and murine models with prostate-specific EHF knockout, loss of EHF expression is sufficient to disrupt luminal identity and induce phenotypic plasticity and multilineage transitions, favoring tumor progression. These findings position EHF as a master regulator of epithelial cell identity and a tractable target for therapeutic cell reprogramming. To test this approach, we have developed mRNA- and DNA-based EHF delivery systems formulated in lipid-polymeric nanoparticles (LPNP) for cell cultures and in vivo administration. The activity of EHF-based constructs was evaluated across a translational preclinical platform including human and murine cell lines, cell line- and patient-derived organoids and xenografts, syngeneic murine allografts, and genetically engineered mouse models. Functional assays and drug combination studies were performed to assess cell differentiation and sensitivity to ARPIs. Multiple molecular, phenotypic, and pharmacodynamic endpoints were analyzed. mRNA- and DNA-based EHF delivery led to efficient and sustained EHF expression in human and murine models and reprogrammed tumor cells toward a luminal differentiation state, restoring canonical AR signaling and responsiveness to AR-directed therapies while suppressing phenotypic plasticity and stem-like features. Functionally, EHF delivery in vitro inhibited proliferation, tumor organoid growth, and tumor sphere formation, without affecting normal epithelial cells. Systemic delivery of LPNP-formulated EHF-encoding mRNA by intravenous injection achieved efficient, sustained, and selective intratumoral EHF expression, resulting in significant tumor growth inhibition in subcutaneous human xenografts and murine allograft models without observable toxicity. Intravenous delivery in mice also enabled efficient target engagement in metastatic lesions in bone and visceral organs, leading to a substantial reduction in metastatic burden. These data establish cell lineage reprogramming via EHF restoration as a novel modality to counteract tumor cell plasticity in prostate cancer. With a defined biomarker framework (low EHF expression, plasticity signatures) and compatibility with various delivery platforms, this approach provides a clear path toward clinical translation. This strategy represents a first-in-class opportunity to target tumor plasticity and overcome resistance in advanced prostate cancer.
Domenico Albino, Carola Musumeci, Elisa Storelli, Atik Balla, Elisa Federici, Gianluca Civenni, Daniela Impellizzieri, Giada Andrea Cassanmagnago, Marco Bolis, Steve Pascolo, Carlo V. Catapano, Giuseppina MR. Carbone. Therapeutic Reversal of Tumor Cell Plasticity by EHF mRNA Delivery in Prostate Cancer [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B014.
D. Albino, C. Musumeci, Elisa Storelli et al.· Clinical Cancer Research· 0 citations
Integrative single-cell RNA sequencing analysis of publicly available datasets from non-small cell lung cancer and breast cancer is performed to systematically map transcriptional heterogeneity and regulatory networks within the TME, providing a systems-level framework of TME organization.
M. O. Odubote, Chiemeka Elochi Emeribe· bioRxiv· 0 citations
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