bims-meproc 2026-04-05 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–04–05
sixteen papers selected by
Grigor Varuzhanyan, UCLA

Interleukin-6 secreted by tumor-associated macrophages promotes proliferation and migration through JAK2/STAT3 signaling pathway in human prostate cancer cells.
Arylpiperazine Derivative NAF19 Inhibits Prostate Cancer Activity and Its Molecular Mechanisms.
ONX-0914 Suppresses Hormone-Sensitive Prostate Cancer by Promoting O-GlcNAcylation-Mediated Stabilization of TCF7L1.
FOXA1 loss drives basal/squamous de-differentiation of prostate cancer and induces an immunosuppressive tumor microenvironment.
Suppression of de novo lipogenesis and dietary PUFA supplementation inhibit prostate cancer progression.
Biobank of genetically defined murine prostate cancer tumoroids uncovers oncogenic pathways and drug vulnerabilities driven by PTEN-loss.
Preclinical activity of SHR-A1921, a novel antibody-drug conjugate targeting trophoblast cell-surface antigen2 (Trop-2) in prostate cancer.
AKR1C3-PKM2-oxidative phosphorylation axis drives prostate cancer radioresistance via UBE2T upregulation.
OTUD4 Inhibits Prostate Cancer by Deubiquitinating MYH9.
Multi-omics integration identifies PGAP3 as a tumor-intrinsic factor associated with CD8+ T-cell exclusion in prostate cancer.
AURKA inhibitor VIC-1911 induces mitotic defects and functional BRCAness, sensitizing prostate cancer to PARP inhibition.
Enhancement of Rotenone Cytotoxicity in the Presence of Bach1 Inhibitors.
Single-stranded DNA in the bone microenvironment promotes prostate cancer bone metastasis via the ITGA6-FAK pathway.
Mapping prostate cancer pathobiology: A review of genetically engineered mouse models (GEMMs).
A single-cell and spatial atlas of prostate cancer reveals the combinatorial nature of gene modules underlying lineage plasticity and metastasis.
Proliferation associates with greater sensitivity to androgen receptor pathway inhibition for metastatic prostate cancer.

Prostate Int. 2026 Mar;14(1): 59-67

Interleukin-6 secreted by tumor-associated macrophages promotes proliferation and migration through JAK2/STAT3 signaling pathway in human prostate cancer cells.

Eunji Seok, Dong Min Lee, Hyunwon Yang, Tag Keun Yoo.

   Background: Tumor-associated macrophages (TAMs) within the tumor microenvironment secrete cytokines that promote cancer progression, proliferation, and metastasis. In prostate cancer, disease progression is closely associated with cytokine activity, particularly interleukin-6 (IL-6), which activates STAT3 to regulate cellular proliferation. Therefore, this study investigated the mechanisms by which TAM-derived IL-6 interacts with prostate cancer cells to affect cancer cell proliferation and metastasis.
Materials and methods: THP-1 monocytes were differentiated into M0 macrophages using phorbol 12-myristate 13-acetate and subsequently co-cultured with conditioned medium (CM) from PC3 prostate cancer cells to induce TAM polarization. Cytokine secretion from TAMs was analyzed using qRT-PCR and cytokine arrays. PC3 cell proliferation, invasion, and migration were evaluated using MTT, Transwell invasion, and wound-healing assays, respectively.
Results: The expression of proliferation-related genes, including TGF-α, TGF-β1, mTOR, FOS, CCND1, and PXN, was assessed using qRT-PCR. The effect of IL-6 on JAK2/STAT3 signaling was examined using western blotting. CM from PC3 cells induced TAM polarization and significantly increased IL-6 expression in TAMs. TAMs enhanced the proliferation, invasion, and migration of PC3 cells, but these effects were suppressed by the STAT3 inhibitor WP1066 and IL-6 neutralizing antibodies. Furthermore, TGF-α and FOS expression was increased in PC3 cells co-cultured with TAMs, but this increase was reduced by WP1066 and IL-6 neutralizing antibody. IL-6 increased the activation of JAK2 and STAT3 proteins in PC3 cells, which was reduced by both treatments.
Conclusions: These findings underscore the role of TAMs in promoting prostate cancer progression through IL-6-mediated JAK2/STAT3 signaling, suggesting the potential of targeting this pathway as a therapeutic strategy for advanced prostate cancer.

Keywords:  Cell migration; Cell proliferation; Interleukin-6; JAK2/STAT3 signaling pathway; Prostate cancer; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.prnil.2025.11.002
Drugs R D. 2026 Apr 03.

Arylpiperazine Derivative NAF19 Inhibits Prostate Cancer Activity and Its Molecular Mechanisms.

Hua Jiang, Mingzhen Xu, Songsong Jiang, Weiqiang Huang.

BACKGROUND AND OBJECTIVES: Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer. However, most patients relapse within 18-24 months, progressing to castration-resistant prostate cancer (CRPC) which is currently incurable. Our preliminary studies identified the arylpiperazine derivative NAF19 as a promising therapeutic agent against prostate cancer, though its precise mechanisms remained unclear. This study aims to systematically evaluate the antitumor effects of NAF19 in prostate cancer cells and elucidate its molecular mechanisms, with a focus on its multi‑target inhibition of the AR/AR‑Vs signaling pathway and key survival pathways.
METHODS: To evaluate the effects of NAF19 on prostate cancer cell growth, we treated a panel of prostate cancer cell lines (LNCaP, C4-2, 22Rv1, DU145, and PC-3) representing both androgen-sensitive and castration-resistant phenotypes (including AR-expressing and AR-null subtypes) with varying concentrations of NAF19 for 72 h. Cell viability and sensitivity were subsequently assessed using the CCK-8 assay. In LNCaP and 22Rv1 cells, we further performed qRT-PCR to analyze the mRNA expression levels of AR/AR-Vs and their downstream target genes (PSA and UBE2C), flow cytometry to determine cell cycle distribution, and western blotting to examine the levels of cleaved PARP, antiapoptotic Bcl-2 family proteins, phosphorylated AKT (at Ser473 and Thr308), phosphorylated ERK, phosphorylated S6, as well as total AR and AR-V7. To assess the impact of NAF19 on tumor cell metastatic potential and proliferation, transwell migration and invasion assays, along with EdU incorporation assays, were conducted. Furthermore, a luciferase reporter assay was carried out to evaluate the transcriptional activity of the androgen receptor (AR).
RESULTS: NAF19 exhibited growth-inhibitory effects across all five prostate cancer cell lines. It significantly suppressed AR/AR-Vs downstream gene expression, induced G1-phase cell cycle arrest in 22Rv1 cells, and reduced anti-apoptotic Mcl-1 protein levels while activating apoptosis. NAF19 dose-dependently induced PARP cleavage; NAF19 significantly reduced the phosphorylation levels of AKT (at T308 and S473 sites), ERK, and S6. Functional assays confirmed marked suppression of migration, invasion, and proliferation in NAF19-treated cells.
CONCLUSIONS: The novel arylpiperazine derivative NAF19 exerts multi-targeted antitumor effects by concurrently inhibiting AR/AR-Vs signaling pathways and activating apoptotic cascades, thereby potently suppressing the migratory, invasive, and proliferative capacities of prostate cancer cells.

DOI: https://doi.org/10.1007/s40268-026-00542-z
Oncol Res. 2026 ;34(4): 31

ONX-0914 Suppresses Hormone-Sensitive Prostate Cancer by Promoting O-GlcNAcylation-Mediated Stabilization of TCF7L1.

Peng Xian, Zhenwei Feng, Haitao Yu, Hubin Yin, Haonan Chen, Tenglin Shi, Xilai Li, Chunlin Zhang, Xuesong Bai, Xin Gou, Xinyuan Li, Jie Li.

   Objective: Androgen receptor (AR) signaling is a central driver of prostate cancer progression, yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized. This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer (HSPC) through metabolic modulation of AR and aimed to identify the transcriptional mediator involved.
Methods: HSPC and castration-resistant prostate cancer models were used to evaluate the effects of ONX-0914 on cell proliferation, invasion, migration, and epithelial-mesenchymal transition. Xenograft assays, bioinformatic screening, and analyses of O-GlcNAcylation and protein stability were performed, together with quantitative polymerase chain reaction (qPCR) and Western blotting.
Results: ONX-0914 markedly suppressed hormone-sensitive prostate cancer (HSPC) progression through both LMP7-dependent and LMP7-independent mechanisms. Mechanistically, ONX-0914 activated the hexosamine biosynthetic pathway and enhanced global O-GlcNAcylation, leading to stabilization of the transcriptional repressor Transcription factor 7-like 1 (TCF7L1) and consequent suppression of androgen receptor (AR) expression. Functionally, activation of the O-GlcNAcylation-TCF7L1 axis inhibited cell proliferation, invasion, migration, and epithelial-mesenchymal transition in vitro. In vivo, TCF7L1 overexpression, particularly under conditions of enhanced O-GlcNAcylation, significantly suppressed tumor growth and AR expression.
Conclusion: This study identifies a novel ONX-0914/HBP/TCF7L1 O-GlcNAcylation axis that metabolically stabilizes TCF7L1, leading to repression of AR signaling and inhibition of HSPC progression. These findings reveal a previously unrecognized metabolic-transcriptional regulatory mechanism and highlight TCF7L1 O-GlcNAcylation as a potential therapeutic target in AR-dependent prostate cancer.

Keywords:  O-GlcNAcylation; Prostate cancer; androgen receptor; hexosamine biosynthetic pathway; transcription factor 7–like 1 (TCF7L1)

DOI:  https://doi.org/10.32604/or.2026.073156
Nat Commun. 2026 Mar 28.

FOXA1 loss drives basal/squamous de-differentiation of prostate cancer and induces an immunosuppressive tumor microenvironment.

Lourdes Brea, Hongshun Shi, Viriya Keo, Jing Huang, Liu Peng, Qi Chu, Wanqing Xie, Yinghua Xie, Sambhavi Senthil, Matthew T Breneman, Jie Fan, Ping Xie, Xiaodong Lu, David J Degraff, Sarki A Abdulkadir, Ximing Yang, David Kosoff, Jonathan C Zhao, Bin Zhang, Jian Hu, Jindan Yu.

FOXA1 is a prostate lineage-specifying transcription factor that is frequently dysregulated or mutated in prostate cancer (PCa). While FOXA1 has been reported to exhibit both PCa-promoting and -inhibitory functions, its role within an immune-proficient PCa context remains unclear. Here, we show that prostate-specific deletion of Foxa1 in Pten-deficient mice drives tumor progression by reprogramming luminal PCa cells toward a basal/squamous-like state and promoting an immunosuppressive tumor microenvironment. Histological and transcriptomic analyses reveal aggressive tumors with extensive basal/squamous features, a reactive stroma, and disorganized tissue architecture. Mechanistically, FOXA1 directly represses basal/squamous and inflammatory genes, which become activated upon its depletion. This is accompanied by an accumulation of immunosuppressive myeloid cells, dysfunctional T cells, and immunosuppressive cytokine signaling. Together, these findings demonstrate a tumor-suppressive role for FOXA1 as an enforcer of luminal identity, such that its loss drives basal/squamous de-differentiation, inflammatory response, and immunosuppression.

DOI: https://doi.org/10.1038/s41467-026-71121-8
bioRxiv. 2026 Mar 27. pii: 2026.03.25.714193. [Epub ahead of print]

Suppression of de novo lipogenesis and dietary PUFA supplementation inhibit prostate cancer progression.

Silvia D Rodrigues, Caroline Fidalgo Ribeiro, Giuseppe N Fanelli, Isadora Ferreira Teixeira, Hubert Pakula, Pier Vitale Nuzzo, Filippo Pederzoli, Fabio Socciarelli, Sara Bleve, Jeanne Jiang, Jonas Dehairs, Guilherme Henrique Tamarindo, Giorgia Zadra, Lisa M Butler, Stephen R Plymate, David W Goodrich, Johannes V Swinnen, David M Nanus, Massimo Loda.

Prostate cancer progression is characterized by dysregulated lipid metabolism, with fatty acid synthase (FASN), the rate-limiting step in de novo lipogenesis (DNL), resulting in significant accumulation of saturated lipids. Here, we investigate whether pharmacologic FASN inhibition creates a metabolic state that increases reliance on exogenous polyunsaturated fatty acids (PUFAs). Inhibition of FASN profoundly alters membrane phospholipid composition, driving compensatory incorporation of PUFAs into membrane phospholipids, thus increasing susceptibility to lipid peroxidation and oxidative damage. Combined FASN inhibition and PUFA exposure increased reactive oxygen species, induced mitochondrial hyperpolarization, and enhanced lipid peroxidation in both hormone-sensitive and castration-resistant prostate cancer models. Marked inhibition of human and murine prostate cancer organoids is achieved ex vivo . In genetically engineered, DNL-reliant Hi-Myc mice, a diet enriched in PUFAs significantly inhibited invasive carcinoma compared to a saturated fat-enriched diet. Environmental PUFAs modulate and enhance the therapeutic efficacy of FASN-targeted strategies. These findings set the stage for pharmacologic and dietary intervention in prostate cancer patients.

DOI: https://doi.org/10.64898/2026.03.25.714193
Cell Rep Methods. 2026 Mar 30. pii: S2667-2375(26)00070-6. [Epub ahead of print] 101370

Biobank of genetically defined murine prostate cancer tumoroids uncovers oncogenic pathways and drug vulnerabilities driven by PTEN-loss.

Jessica Kalla, Thomas Dillinger, Zlata Pavlovicova, Reema Jacob, Emine Atas, Katarina Mišura, Anil Baskan, Kristina Draganić, Andreas Tiefenbacher, Tanja Limberger, Theresia Mair, Gabriel Wasinger, Ludovica Villanti, Stefan Kubicek, Lukas Kenner, Gerda Egger.

  Prostate cancer (PCa) is the second most common cancer in men and shows high inter- and intra-patient heterogeneity. Consequently, treatment options are limited and there is a lack of representative preclinical models. Here, we establish a comprehensive biobank of murine organoids and tumoroids that reflect common patient mutations. We demonstrate that the deletion of Pten alone, or in combination with Stat3, or Tp53, drives the activation of cancer-related pathways in both prostate organoids and tumor-derived tumoroids. A medium-throughput drug screen identified two potent compounds, the PDPK1/AKT/FLT dual pathway inhibitor and the sirtuin inhibitor tenovin-6, which effectively suppressed tumoroid proliferation. Notably, these compounds also inhibited the growth of several human PCa cell lines and displayed synergistic effects when combined with the standard-of-care antiandrogen enzalutamide. Together, our findings provide evidence that murine tumoroids are versatile preclinical models for studying PCa tumorigenesis and drug sensitivities to develop therapeutic options for PCa patients.

Keywords:  CP: biotechnology; CP: molecular biology; PDPK1/AKT/FLT dual pathway inhibitor; PI3K/AKT signaling; drug screen; mouse models; organoids; preclinical models; prostate cancer; tenovin-6; tumoroids

DOI:  https://doi.org/10.1016/j.crmeth.2026.101370
Front Pharmacol. 2026 ;17 1713983

Preclinical activity of SHR-A1921, a novel antibody-drug conjugate targeting trophoblast cell-surface antigen2 (Trop-2) in prostate cancer.

Binyu Wang, Qiuya Xu, Shan Peng, Zheng Han, Haifeng Huang, Hongqian Guo, Xuefeng Qiu.

   Background: Despite advances in the 5-year survival rates for prostate cancer patients, progression to metastatic castration-resistant prostate cancer (mCRPC) remains a significant challenge following standard treatments. Antibody-drug conjugates (ADCs) are an emerging class of biopharmaceuticals that combine the specificity of monoclonal antibodies with the potency of cytotoxic drugs. Trophoblast cell surface antigen 2 (Trop-2) is overexpressed in prostate cancer, particularly in metastatic forms.
Methods: Response to this, we developed a novel Trop-2-targeted antibody-drug conjugate (ADC), SHR-A1921, which incorporates a potent DNA topoisomerase I inhibitor,SHR9265. Its in vitro cytotoxicity was assessed across prostate cancer cell lines with differential Trop-2 expression. Subcutaneous xenograft models were established for in vivo tumor-suppressive activity evaluation, and patient-derived organoid models validated its potential clinical efficacy.
Results: In preclinical models, SHR-A1921 specifically bound to Trop-2, followed by internalization into tumor cells and subsequent intracellular trafficking to lysosomes, where the release of SHR9265 occurred. This resulted in DNA damage and apoptosis in Trop-2-expressing tumor cells in vitro. In vivo, SHR-A1921 exhibited significant antitumor activity, inducing DNA damage in Trop-2-positive xenograft tumors. Additionally, SHR-A1921 demonstrated antitumor effects in Trop-2-expressing prostate cancer organoids. Safety assessments in rats indicated that SHR-A1921 had an acceptable safety profile.
Conclusion: SHR-A1921 is a promising Trop-2-targeted ADC that leverages innovative technology to deliver potent antitumor activity against Trop-2-expressing prostate cancer cells, with an acceptable safety profile observed in preclinical studies. These results highlight the promising clinical potential of SHR-A1921 as a therapeutic option for prostate cancer patients with Trop-2-positive tumors.

Keywords:  SHR-A1921; Trop-2; antibody-drug conjugates; patient-derived organoids; prostate cancer; targeted therapy

DOI:  https://doi.org/10.3389/fphar.2026.1713983
Cell Death Dis. 2026 Mar 30.

AKR1C3-PKM2-oxidative phosphorylation axis drives prostate cancer radioresistance via UBE2T upregulation.

Jinyu Zhang, Jiongzheng Li, Yufei Yan, Binghuan Wang, Ruojia Wang, Xiaoli Cui, Yang Zhan, Zuowen Liang, Jing Li.

Radioresistance is one of the primary causes of prostate cancer treatment failure and post-radiotherapy progression. However, there is currently a lack of effective targets to increase radiotherapy sensitivity and inhibit malignant progression. We identified AKR1C3 as a potential key target associated with radioresistance and malignant progression through integrated bioinformatic analysis of RNA sequencing (RNA-seq) data from prostate cancer clinical samples in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The promotion of radioresistance by AKR1C3 in both AR-positive and AR-negative prostate cancer cells was further validated through in vivo and in vitro experiments. Mechanistic studies revealed that AKR1C3 can bind to PKM2 and accelerate its degradation, thereby inhibiting glycolytic flux and enhancing oxidative phosphorylation (OXPHOS). Increased OXPHOS boosts ROS production, which further promotes NRF2 nuclear translocation, activating the transcription of DNA repair protein UBE2T. This enhanced DNA damage repair ability enables prostate cancer cells with high AKR1C3 expression to exhibit greater resistance to radiotherapy. In summary, this study reveals the molecular mechanism by which AKR1C3 is involved in metabolic reprogramming to promote radioresistance in prostate cancer through PKM2/UBE2T. These findings indicate that targeting AKR1C3 has potential for overcoming radioresistance, providing novel insight into the clinical treatment of prostate cancer.

DOI: https://doi.org/10.1038/s41419-026-08666-5
Oncol Res. 2026 ;34(4): 32

OTUD4 Inhibits Prostate Cancer by Deubiquitinating MYH9.

Zheng Qin, Yueyao Zhang, Dongze Liu, Xiaokang Zheng, Kaibin Wang, Xiao Zhu, Yuanhao Zhang, Kexin Xu, Changying Li, Lijuan Kang, Lili Wang, Haitao Wang.

   Objective: Prostate cancer is the second most common fatal cancer in men. Identifying new biological therapeutic targets is crucial to effectively improve the prognosis of prostate cancer patients. Ovarian tumor family deubiquitinase 4 (OTUD4) is a member of the ovarian tumor-associated protease domain (OTUDs) family. Although previous studies have shown that the expression and function of OTUD4 vary across different tumors, its role in prostate cancer remains unknown. The aim of this study is to explore new therapeutic targets and diagnostic markers for prostate cancer and investigate their mechanisms of action.
Methods: Cell culture, Cell Counting Kit-8 (CCK-8) assay, colony formation assay, Transwell assay, 5-Ethynyl-2'-deoxyuridine (EdU) assay, immunofluorescence, Western blot, Quantitative real-time PCR (qRT-PCR), protein mass spectrometry, nude mouse xenograft models, immunohistochemistry (IHC), and hematoxylin and eosin (H&E) staining were utilized.
Results: We found that OTUD4 expression was reduced in prostate cancer and negatively correlated with poor prognosis in both in vivo and in vitro experiments. Subsequent mechanistic studies revealed that OTUD4 directly inhibits the degradation of myosin-9 (MYH9) protein via deubiquitination. Although MYH9 has been previously reported to act as a tumor suppressor in prostate cancer, no experimental evidence had demonstrated that MYH9 inhibits prostate cancer growth. Our results indicate that MYH9 overexpression effectively suppresses prostate cancer through interactions with cell adhesion molecules.
Conclusion: Collectively, these results suggest that OTUD4 functions as a tumor suppressor in prostate cancer. Specifically, OTUD4 inhibits MYH9 degradation via deubiquitination, thereby enabling MYH9-mediated suppression of prostate cancer.

Keywords:  Prostate cancer; myosin-9 (MYH9); ovarian tumor family deubiquitinase 4 (OTUD4); therapeutic target; ubiquitin (UB)

DOI:  https://doi.org/10.32604/or.2025.073455
Front Mol Biosci. 2026 ;13 1791456

Multi-omics integration identifies PGAP3 as a tumor-intrinsic factor associated with CD8+ T-cell exclusion in prostate cancer.

Weihao Liu, Guoping Li, Yan Lei, Huixiu Liu, Binhui Wang, Weiming Deng, Yude Hong, Xiangyang Long.

   Background: Prostate cancer (PCa) is prototypically immunologically "cold", characterized by low tumor mutational burden, sparse CD8+ T-cell infiltration, and resistance to immune checkpoint blockade. The tumor cell-intrinsic programs driving immune evasion in this context remain incompletely defined.
Methods: We integrated transcriptome-wide Mendelian randomization of PCa GWAS and eQTL data with multi-cohort bulk and single-cell RNA sequencing, spatial transcriptomics, and immune profiling to prioritize candidate genes. Focusing on PGAP3, we characterized its metabolic and immune correlates, and validated the effects of PGAP3 knockdown on proliferation, clonogenicity, and migration in C4-2 and DU145 cells.
Results: PGAP3 was consistently prioritized as a risk gene and was selectively overexpressed in malignant epithelial subpopulations. PGAP3-high cells exhibited increased metabolic activity (biotin, aspartate/asparagine, and sulfur metabolism), coinciding with reduced CXCL14, TNFSF13B, and TNFSF18 expression, lower CD8+ T-cell infiltration, and higher immune-exclusion scores. Functionally, PGAP3 silencing significantly impaired proliferation, clonogenic growth, and migration in vitro.
Conclusion: Our findings identify PGAP3 as a tumor-intrinsic gene associated with metabolic reprogramming and a CTL/CD8+-low immune contexture in PCa, supporting PGAP3 as a potential marker of the immune-cold tumor microenvironment and motivate future mechanistic studies in immunocompetent systems.

Keywords:  CD8+ T-cell exclusion; Mendelian randomization; PGAP3; multi-omics; prostate cancer; tumor microenvironment

DOI:  https://doi.org/10.3389/fmolb.2026.1791456
JCI Insight. 2026 Mar 31. pii: e196665. [Epub ahead of print]

AURKA inhibitor VIC-1911 induces mitotic defects and functional BRCAness, sensitizing prostate cancer to PARP inhibition.

Galina Gritsina, Sandip Kumar Rath, Hongshun Shi, Qi Chu, Wanqing Xie, Que Thanh Thanh Nguyen, Sambhavi Senthil, Thomas J Myers, Mehmet A Bilen, Sarah E Fenton, Maha Hussain, David S Yu, Jonathan C Zhao, Jindan Yu.

  VIC-1911 (formerly TAS-119) is a next-generation, ATP-competitive Aurora kinase A (AURKA) inhibitor with a favorable biosafety profile. However, it has not been evaluated in prostate cancer (PC), wherein AURKA is highly expressed in advanced stages and represents a critical therapeutic target. Here, we demonstrate that VIC-1911 potently inhibits AURKA activity with high selectivity over AURKB/C across diverse PC cell lines. Treatment with VIC-1911, even at nanomolar concentrations, substantially inhibits the growth of both androgen receptor (AR)-positive and AR-negative PC cells. VIC-1911 triggers mitotic failure, induces DNA double-strand breaks (DSBs), and activates the p53 pathway, halting cell division and inducing cell death. Notably, VIC-1911 showed synergistic effects in inhibiting PC cell growth in vitro and xenograft tumor growth in vivo with poly (ADP-ribose) polymerase inhibitors (PARPi), which have proven effective in PC with a deficiency in Homologous Recombination (HR) repair. Mechanistically, VIC-1911 disabled HR-mediated repair of DSBs in otherwise HR-proficient PC cells, leading to a "BRCAness" phenotype and pronounced accumulation of DNA damage and mitotic catastrophe. In summary, our study uncovers what we believe a novel mechanism to functional "BRCAness" by inducing mitotic arrest and highlights VIC-1911 as a promising therapeutic agent for advanced PC, either as a single agent or in combination, sensitizing HR-proficient tumors to PARP inhibitors.

Keywords:  DNA repair; Drug therapy; Genetics; Oncology; Prostate cancer

DOI:  https://doi.org/10.1172/jci.insight.196665
Dokl Biochem Biophys. 2026 Mar 30.

Enhancement of Rotenone Cytotoxicity in the Presence of Bach1 Inhibitors.

S V Nikulin, D Olkhovik, A V Razumovskaya, M O Silkina, A A Zakhariants, K V Klycheva, G A Khairetdinova, I G Gazaryan, D M Hushpulian.

  A novel trend in anticancer therapy is based on the combination of cytotoxic and metabolic drugs. Bach1 is a transcription factor activating glycolysis and increasing proliferation and metastatic potential in cancer cells. The cytotoxic effect was evaluated for a combination of rotenone, an inhibitor of mitochondrial respiration, and two different inhibitors of Bach1 transcription factor in the prostate cancer cell lines (PC3 and Du145) and colorectal cancer (HT-29 and HCT-116) in a kinetic mode. An enhancement of the cytotoxic action of the combination therapy was observed only for the prostate cancer cell lines PC3 and Du145. No enhancement of cytotoxicity of zinc porphyrin in the presence of rotenone was observed for the НСТ-116 line. The HT-29 line was not sensitive to either inhibitor or their combination with rotenone at 24 h incubation. According to the PCR results, HT-29 was the only line showing an extremely high activation of heme oxygenase 1 (HMOX1) in the presence of the Bach1 inhibitor, pointing to the highest level of the antioxidant defense in this cell line. The sensitivity of the prostate cancer cell lines to the combination therapy points to the significant differences in the metabolism between the prostate and colorectal cell lines.

Keywords:  Bach1; HPPE; colorectal cancer; heme oxygenase 1; prostate cancer; rotenone

DOI:  https://doi.org/10.1134/S1607672925601817
Commun Biol. 2026 Mar 31.

Single-stranded DNA in the bone microenvironment promotes prostate cancer bone metastasis via the ITGA6-FAK pathway.

Xin Chen, Ming-Sheng Ye, Zhuo-Lin Peng, Feng Yan, Yuan Xiao, Yu-Jue Li, Ye Xiao.

Bone metastases represent a critical phenotype of prostate cancer progression, driven by factors within the bone microenvironment. However, the molecular mechanisms underlying this progression remain poorly understood. In this study, we observed a significant accumulation of single-stranded DNA within the metastatic bone microenvironment of PCa patients. Through cell-SELEX methodology, we identified a PCa target-specific ssDNA, EHBP1. Specifically, EHBP1-ssDNA specifically captures PCa cells by binding to the transmembrane protein integrin α6, which subsequently activates the integrin α6-FAK signaling pathway. Functional studies revealed that knockdown of integrin-α6 expression effectively abrogated EHBP1-ssDNA mediated PCa bone metastatic capacity. Notably, these findings were recapitulated through pharmacological inhibition of FAK signaling using Defactinib, an FAK-specific inhibitor. Taken together, our findings reveal that bone-marrow ssDNA may represent a bone microenvironment factor that captures and promotes PCa homing to bone, further suggesting a potential therapeutic strategy for mitigating bone metastasis.

DOI: https://doi.org/10.1038/s42003-026-09929-9
Gene. 2026 Mar 27. pii: S0378-1119(26)00141-1. [Epub ahead of print]996 150131

Mapping prostate cancer pathobiology: A review of genetically engineered mouse models (GEMMs).

Filippo Pederzoli, Hubert Pakula, Silvia Rodrigues, Richard Garner, Pier Vitale Nuzzo, Sara Bleve, David S Rickman, Giuseppe Nicolò Fanelli, Massimo Loda.

  Prostate cancer (PCa) is the second most common malignancy in men and represents about 7% of newly diagnosed tumors worldwide (and up to 15% in developed countries). At the genomic level, PCa is generally characterized by copy number alterations and/or gene structural rearrangements that encompass multiple genes, including oncogenes such as ERG and MYC and tumor suppressor genes such as TP53 and PTEN. To advance our understanding of the role of specific genomic alterations in PCa, genetically engineered mouse models (GEMMs) have been pivotal in complementing large-scale human sequencing initiatives. In this Review, we focus on the main altered genes in PCa and how they have been modeled in different GEMMs to study the molecular mechanisms underlying PCa tumorigenesis and progression.

Keywords:  GEMMs; Genetically engineered mouse models; Genomic alterations; Prostate cancer; Transgenic mice

DOI:  https://doi.org/10.1016/j.gene.2026.150131
bioRxiv. 2026 Mar 27. pii: 2026.03.25.711335. [Epub ahead of print]

A single-cell and spatial atlas of prostate cancer reveals the combinatorial nature of gene modules underlying lineage plasticity and metastasis.

Hanbing Song, Junxiang Xu, Keila Velazquez-Arcelay, Arda Demirci, Brendan L Raizenne, Sarah C Hsu, Joshua Choi, Julia H Pham, Yih-An Chen, Hannah N W Weinstein, Isaac Salzman, Margaret Tsui, Jon Akutagawa, Wisdom Adingo, Ezequiel Goldschmidt, Peter R Carroll, Julian C Hong, Christopher M Heaphy, Matthew R Cooperberg, Nancy Greenland, Joshua D Campbell, Franklin W Huang.

Prostate cancer encompasses a spectrum of disease states driven by complex cellular heterogeneity. To delineate the transcriptional programs underlying lineage plasticity and metastasis, we constructed a comprehensive single-cell atlas of 128 patients, spanning localized, castration-resistant, and metastatic disease. Lineage plasticity was prevalent in localized disease, with subsets of tumor cells adopting distinct basal-like and club-like states. Luminal-like cancer cells also displayed extensive lineage infidelity, defined not by a binary loss of identity but by the combinatorial erosion of luminal gene modules associated with higher grade and stage. In the metastatic setting, gene program association analysis (GPAS) identified a broad induction of cell-cycle gene modules across organ sites as well as an induction of organ-specific gene modules, including osteomimetic signaling in bone, neuro-migratory genes in brain, and erythroid-like transitions in liver. Neuroendocrine prostate cancers (NEPCs) were not monolithic but defined by combinations of NE-associated gene modules including a novel HES6 program. Notably, these modules were detected at intermediate levels in localized samples, suggesting molecular plasticity precedes histological transformation. We also developed a refined NE signature that could distinguish NEPC tumors more accurately than previously published signatures. Within the tumor microenvironment (TME), we observed an elevation of pro-inflammatory Th17 T-cells in African American patients and identified a rare Schwann cell population. Finally, we present PCformer, a transformer-based foundation model trained on >500,000 cells to automate cell-state classification. Together, this comprehensive atlas demonstrates the complex nature of gene modules underlying lineage infidelity and plasticity in cancer cells and highlights distinct immune and stromal populations within the tumor ecosystem.

DOI: https://doi.org/10.64898/2026.03.25.711335
J Clin Invest. 2026 Mar 31. pii: e203201. [Epub ahead of print]

Proliferation associates with greater sensitivity to androgen receptor pathway inhibition for metastatic prostate cancer.

Larissa Mendes, Peter F Dutey-Magni, Emily Grist, Ashwin Sachdeva, Sara Santos Vidal, Sharanpreet Lall, Marina A Parry, Claire L Amos, Nafisah B Atako, Anna Wingate, Daniel Wetterskog, Matthew R Sydes, Chris C Parker, Noel Clarke, Christopher J Sweeney, Mahesh Kb Parmar, Louise C Brown, Nicholas D James, Daniel M Berney, Gerhardt Attard.

  BACKGROUND Proliferation is a key biological feature of cancer and in prostate cancer is modulated by androgen receptor (AR) signalling. Cohort studies have suggested that highly proliferative tumors respond poorly to androgen receptor pathway inhibitors (ARPIs). To clarify whether tumor proliferation interacts with treatment benefit from adding abiraterone to androgen deprivation therapy (ADT), we assessed the Ki-67 proliferation index in prostate core biopsies from participants enrolled in the STAMPEDE platform protocol. METHODS Proliferation was assessed by Ki67 immunohistochemistry on tumors from patients randomized in two sequential but non-overlapping (ie no shared controls) phase 3 trials of abiraterone or abiraterone and enzalutamide conducted in STAMPEDE (NCT00268476), with 14-year survival outcomes. A standardised unweighted global assessment method was used. Survival analyses used Cox proportional hazards models adjusted for established prognostic factors. Ki-67 was examined both continuously and dichotomised at the median. Sensitivity analyses excluded samples exposed to ADT. RESULTS Ki-67 was successfully scored on cancers from 1,605 patients. Higher Ki-67 was strongly prognostic for shorter overall survival across disease states. However, in metastatic patients treated with ADT plus abiraterone, the adverse prognostic impact of high Ki-67 was substantially attenuated (aHR=1.06 per 10-percentage-point increase), with a statistically-significant treatment-biomarker interaction (p<0.001) confirming highly proliferative tumors derived greater treatment benefit. No interaction was observed in non-metastatic disease. CONCLUSION Ki-67 is an independent prognostic biomarker in advanced prostate cancer. In metastatic disease, higher proliferation predicts greater sensitivity to abiraterone added to ADT, suggesting a potential biological vulnerability of rapidly cycling tumors to intensified AR pathway blockade. TRIAL REGISTRATION: NCT00268476.

Keywords:  Biomarkers; Clinical Research; Clinical trials; Oncology; Prostate cancer

DOI:  https://doi.org/10.1172/JCI203201