Biology subjects

Nanus, D. M.

Publications and source records attributed to Nanus, D. M..

5 recordsLinked to original sources

bioRxiv2026

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

Prostate cancer progression is characterized by dysregulated lipid metabolism, with activation of fatty acid synthase (FASN), the rate-limiting step in de novo lipogenesis (DNL), resulting in significant accumulation of saturated lipids. Here, we show that 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 induce mitochondrial hyperpolarization and enhance lipid peroxidation in both hormone-sensitive and castration-resistant prostate cancer models, resulting in increased reactive oxygen species production, ferroptosis, as well as apoptosis. Marked inhibition of growth in castration-resistant 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. Thus, 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.

cancer biology↗

bioRxiv2025

TMPO promotes cellular dissemination and metastasis in circulating tumor cells

Metastasis--the process by which cancer cells spread beyond the primary tumor to distant organs--accounts for the vast majority of cancer-related deaths. To elucidate mechanisms underlying dissemination and metastasis in prostate cancer, we have investigated circulating tumor cells (CTCs) obtained from genetically engineered mouse models (GEMMs). The phenotypic and molecular properties of the CTCs, and organoids derived from these CTCs, closely model the tumor and metastatic phenotypes of their parental GEMMs. Moreover, organoids derived from individual CTCs exhibit molecular and morphological heterogeneity that is associated with distinct metabolic states as well as differences in human prostate cancer outcome. Using computational systems analyses, we have identified TMPO, encoding the nuclear membrane protein lamina-associated polypeptide 2 (Lap2), as a key driver of this heterogeneity. TMPO activity is upregulated in advanced human prostate tumors, metastases, and CTCs, and is associated with adverse clinical outcome. Our findings indicate that TMPO promotes dissemination and metastasis in vivo by enhancing survival in conditions of metabolic stress, and reveal a novel mechanistic link between CTC heterogeneity, stress adaptation, and metastatic potential.

cell biology↗

bioRxiv2023

The Interplay between Mutagenesis and Extrachromosomal DNA Shapes Urothelial Cancer Evolution

Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity. In this study, we investigate the evolution of the genomic signatures caused by endogenous and external mutagenic stimuli and their interplay with complex structural variants. We superimposed mutational signatures and phylogenetic analyses of matched serial tumors from patients with urothelial cancer to define the evolutionary patterns of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas mutational bursts comprising hundreds of late subclonal mutations are induced by chemotherapy. Using a novel genome graph computational paradigm, we observed frequent circular high copy-number amplicons characteristic of extrachromosomal DNA (ecDNA) involving double-minutes, breakage-fusion-bridge, and tyfonas events. We characterized the distinct temporal patterns of APOBEC3 mutations and chemotherapy-induced mutations within ecDNA, gaining new insights into the timing of these events relative to ecDNA biogenesis. Finally, we discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA amplicons. These CCND1 ecDNA amplification events persisted and increased in complexity incorporating additional DNA segments potentially contributing selective fitness advantage to the evolution of treatment resistance. Our findings define fundamental mechanisms driving urothelial cancer evolution and have therapeutic implications for treating this disease.

genomics↗

bioRxiv2021

AR-V7 exhibits non-canonical mechanisms of nuclear import and chromatin engagement in Castrate-Resistant Prostate Cancer

Expression of the AR splice variant, AR-V7, in prostate cancer is correlated with poor patient survival and resistance to AR targeted therapies and taxanes. Currently, there is no specific inhibitor of AR-V7, while the molecular mechanisms regulating its biological function are not well elucidated. Here we report that AR-V7 has unique biological features that functionally differentiate it from canonical AR-fl or from the second most prevalent variant, AR-v567. First, AR-V7 exhibits fast nuclear import kinetics via a pathway distinct from the nuclear localization signal dependent importin- /{beta} pathway used by AR-fl and AR-v567. We also show that the dimerization box domain, known to mediate AR dimerization and transactivation, is required for AR-V7 nuclear import but not for AR-fl. Once in the nucleus, AR-V7 is transcriptionally active, yet exhibits unusually high intranuclear mobility and transient chromatin interactions, unlike the stable chromatin association of liganded AR-fl. The high intranuclear mobility of AR-V7 together with its high transcriptional output, suggest a Hit-and-Run mode of transcription. Our findings reveal unique mechanisms regulating AR-V7 activity, offering the opportunity to develop selective therapeutic interventions.

cancer biology↗

bioRxiv2019

Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells

Aberrant neuroendocrine signaling is frequent yet poorly understood feature of prostate cancers. Membrane metalloendopeptidase (MME) is responsible for the catalytic inactivation of neuropeptide substrates, and is downregulated in nearly 50% of prostate cancers. However its role in prostate carcinogenesis, including formation of castration-resistant prostate carcinomas, remains uncertain. Here we report that MME cooperates with PTEN in suppression of carcinogenesis by controlling activities of prostate stem/progenitor cells. Lack of MME and PTEN results in development of adenocarcinomas characterized by propensity for vascular invasion and formation of proliferative neuroendocrine clusters after castration. Effects of MME on prostate stem/progenitor cells depend on its catalytic activity and can be recapitulated by addition of the MME substrate, gastrin-releasing peptide (GRP). Knockdown or inhibition of GRP receptor (GRPR) abrogate effects of MME deficiency, and delay growth of human prostate cancer xenografts by reducing the number of cancer propagating cells. In sum, our study provides a definitive proof of tumor suppressive role of MME, links GRP/GRPR signaling to the control of prostate stem/progenitor cells, and shows how dysregulation of such signaling may promote formation of castration-resistant prostate carcinomas. It also identifies GRPR as a valuable target for therapies aimed at eradication of cancer propagating cells in prostate cancers with MME downregulation.

cancer biology↗