@article{835bfa9e650d45ddbfe69707602d54f0,
title = "ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer",
abstract = "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 SCLC models and directly regulates multiple DepMap-defined essential genes. We provide LTF/SE-based subtype-specific gene sets for SCLC for further therapeutic investigation.",
keywords = "bioinformatics, cancer systems biology, molecular biology",
author = "Karine Pozo and Kollipara, {Rahul K.} and Kelenis, {Demetra P.} and Rodarte, {Kathia E.} and Ullrich, {Morgan S.} and Xiaoyang Zhang and Minna, {John D.} and Johnson, {Jane E.}",
note = "Funding Information: We acknowledge the many helpful discussions with members of the SCLC interest group at UT Southwestern, Chaoying Liang in the Microarray Core at UT Southwestern for Next Generation Sequencing and Mohammad Goodarzi in the Proteomics Core facility at UT Southwestern for outstanding service. We thank Victor Stastny, Kenneth Huffman, Luc Girard, and Adi Gazdar (deceased) for work on the SCLC lines and discussions about SCLC lineage transcription factors, and Charles Rudin and J.T. Poirier for providing the SCLC PDX. Support for maintaining, authentication, and genomic characterization of the SCLC cell lines was provided in part by NCI U24CA213274. Funding for this project was provided by the NCI including U01CA213338 to J.D.M. R00 CA215244 to X.Z, a Career Development Award from the Spore Grant in Lung Cancer P50CA70907 to K.P. F30 CA228314 to D.P.K, and the Cancer Prevention Research Institute of Texas Training Grant RP160157 to K.R. Conceptualization, K.P. and J.E.J.; investigation, K.P. K.E.R. D.P.K. M.S.U. and X.Z.; formal analysis, R.K.K.; resources, J.E.J. J.D.M. and X.Z.; writing-original draft, K.P. R.K.K. and J.E.J.; writing-review & editing, K.P. R.K.K. K.E.R. D.P.K. M.S.U. X.Z. J.D.M. and J.E.J.; funding acquisition, K.P. J.E.J. X.Z. and J.D.M; supervision, J.E.J. J.D.M. receives licensing fees for lung cancer lines from the NIH and UT Southwestern Medical Center. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. Funding Information: We acknowledge the many helpful discussions with members of the SCLC interest group at UT Southwestern, Chaoying Liang in the Microarray Core at UT Southwestern for Next Generation Sequencing and Mohammad Goodarzi in the Proteomics Core facility at UT Southwestern for outstanding service. We thank Victor Stastny, Kenneth Huffman, Luc Girard, and Adi Gazdar (deceased) for work on the SCLC lines and discussions about SCLC lineage transcription factors, and Charles Rudin and J.T. Poirier for providing the SCLC PDX. Support for maintaining, authentication, and genomic characterization of the SCLC cell lines was provided in part by NCI U24CA213274 . Funding for this project was provided by the NCI including U01CA213338 to J.D.M., R00 CA215244 to X.Z, a Career Development Award from the Spore Grant in Lung Cancer P50CA70907 to K.P., F30 CA228314 to D.P.K, and the Cancer Prevention Research Institute of Texas Training Grant RP160157 to K.R. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = sep,
day = "24",
doi = "10.1016/j.isci.2021.102953",
language = "English (US)",
volume = "24",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "9",
}