Biology subjects

Denize, T.

Publications and source records attributed to Denize, T..

3 recordsLinked to original sources

bioRxiv2023

Spatially aware deep learning reveals tumor heterogeneity patterns that encode distinct kidney cancer states

Background Abstract Background Results Discussion Methods Data Availability Code Availability Author Contributions Competing Interests Extended Data References Renal cell carcinoma (RCC) is among the 10 most common cancers worldwide and is comprised of several histological subtypes1. The clear cell histological subtype (ccRCC) is the most common form of RCC and accounts for the vast majority (75-80%) of metastatic cases1. In addition to highly recurrent mutations in hypoxia (VHL) and chromatin regulator genes (e.g. PBRM1, BAP1, SETD2), ccRCC exhibits extensive genomic intratumoral heterogeneity (ITH)2, which wa ...

cancer biology↗

bioRxiv2021

Regulation of Neuroendocrine Plasticity by the RNA-Binding Protein ZFP36L1

Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 inhibitors are thought to induce their anti-proliferative effects by blocking neuroendocrine differentiation, but the mechanisms by which LSD1 controls the SCLC neuroendocrine phenotype are not well understood. To identify genes required for LSD1 inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss of function screen and found that ZFP36L1, an mRNA-binding protein that destabilizes mRNAs, is required for LSD1 inhibitor sensitivity. LSD1 binds and represses ZFP36L1 and upon LSD1 inhibition, ZFP36L1 expression is restored, which is sufficient to block the SCLC neuroendocrine differentiation phenotype and induce a non-neuroendocrine "inflammatory" phenotype. Mechanistically, ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs, two transcription factors that are required for SCLC neuroendocrine differentiation. This work identifies ZFP36L1 as an LSD1 target gene that controls the SCLC neuroendocrine phenotype and demonstrates that modulating mRNA stability of lineage transcription factors controls neuroendocrine to non-neuroendocrine plasticity.

cancer biology↗

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↗