Journal
ISCIENCE
Volume 24, Issue 9, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.isci.2021.102953
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Categories
Funding
- NCI [U01CA213338, R00 CA215244, U24CA213274]
- Spore Grant in Lung Cancer [P50CA70907, F30 CA228314]
- Cancer Prevention Research Institute of Texas Training Grant [RP160157]
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Lineage-defining transcription factors play key roles in small-cell lung cancer pathophysiology, and specific gene sets associated with super-enhancers can help identify dependencies in SCLC. In ASCL1-high SCLC, ASCL1 complexes with NKX2-1 and PROX1 to co-regulate genes functioning in critical biological processes such as NOTCH signaling.
Lineage-defining transcription factors (LTFs) play key roles in small-cell lung cancer (SCLC) pathophysiology. Delineating the LTF-regulated genes operative in SCLC could provide a road map to identify SCLC dependencies. We integrated chromatin landscape and transcriptome analyses of patient-derived SCLC preclinical models to identify super-enhancers (SEs) and their associated genes in the ASCL1-, NEUROD1-, and POU2F3-high SCLC subtypes. We find SE signatures predict LTF-based classification of SCLC, and the SE-associated genes are enriched with those defined as common essential genes in DepMap. In addition, in ASCL1-high SCLC, we show ASCL1 complexes with NKX2-1 and PROX1 to co-regulate genes functioning in NOTCH signaling, catecholamine biosynthesis, and cell-cycle processes. Depletion of ASCL1 demonstrates it is a key dependency factor in preclinical SCLCmodels and directly regulatesmultiple DepMap-defined essential genes. We provide LTF/SE-based subtype-specific gene sets for SCLC for further therapeutic investigation.
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