Biology subjects

Metaferia, N. Y.

Publications and source records attributed to Metaferia, N. Y..

2 recordsLinked to original sources

bioRxiv2021

Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma

ABSTRACTTranslocation renal cell carcinoma (tRCC) is an aggressive and poorly-characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 tRCC patients identified across multiple genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to many targeted therapies. Consistently, we find that outcomes for tRCC patients treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKI) are worse than those treated with immune checkpoint inhibition (ICI). Multiparametric immunofluorescence confirmed the presence of CD8 + tumor-infiltrating T cells compatible with a clinical benefit from ICI and revealed an exhaustion immunophenotype distinct from clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

cancer biology↗

bioRxiv2020

Genome-scale genetic screening identifies PRMT1 as a critical vulnerability in castration-resistant prostate cancer

Androgen receptor (AR) signaling is the central driver of prostate cancer across disease states. While androgen deprivation therapy (ADT) is effective in the initial treatment of prostate cancer, resistance to ADT or to next-generation androgen pathway inhibitors invariably arises, most commonly through re-activation of the AR axis. Thus, orthogonal approaches to inhibit AR signaling in advanced prostate cancer are essential. Here, via genome-scale CRISPR/Cas9 screening, we identify protein arginine methyltransferase 1 (PRMT1) as a critical mediator of AR expression and signaling. PRMT1 regulates recruitment of AR to genomic target sites and inhibition of PRMT1 impairs AR binding at lineage-specific enhancers, leading to decreased expression of key oncogenes, including AR itself. Additionally, AR-driven prostate cancer cells are uniquely susceptible to combined AR and PRMT1 inhibition. Our findings implicate PRMT1 as a key regulator of AR output and provide a preclinical framework for co-targeting of AR and PRMT1 in advanced prostate cancer.

cancer biology↗