ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer
Karine Pozo,
Rahul K. Kollipara,
Demetra P. Kelenis,
Kathia E. Rodarte,
Morgan S. Ullrich,
Xiaoyang Zhang,
John D. Minna,
Jane E. Johnson
Affiliations
Karine Pozo
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
Rahul K. Kollipara
McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA
Demetra P. Kelenis
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA
Kathia E. Rodarte
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA
Morgan S. Ullrich
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA
Xiaoyang Zhang
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
John D. Minna
Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA
Jane E. Johnson
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author
Summary: 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.
