title: ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs.
abstract: Small cell lung carcinoma (SCLC) is a high-grade pulmonary neuroendocrine tumor. The transcription factors ASCL1 and NEUROD1 play crucial roles in promoting malignant behavior and survival of human SCLC cell lines. Here, we find that ASCL1 and NEUROD1 identify heterogeneity in SCLC, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1, but not NEUROD1, is present in mouse pulmonary neuroendocrine cells, and only ASCL1 is required in vivo for tumor formation in mouse models of SCLC. ASCL1 targets oncogenic genes including MYCL1, RET, SOX2, and NFIB while NEUROD1 targets MYC. ASCL1 and NEUROD1 regulate different genes that commonly contribute to neuronal function. ASCL1 also regulates multiple genes in the NOTCH pathway including DLL3. Together, ASCL1 and NEUROD1 distinguish heterogeneity in SCLC with distinct genomic landscapes and distinct gene expression programs.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Borromeo
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Trisha K
authors.initials: TK
authors.lastname: Savage
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Rahul K
authors.initials: RK
authors.lastname: Kollipara
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Augustyn
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jihan K
authors.initials: JK
authors.lastname: Osborne
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Cobb
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: jane.johnson@utsouthwestern.edu.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Johnson
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D055099:Neuroendocrine Cells / Q000378:metabolism; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C499317:Ascl1 protein, mouse; C501008:Neurod1 protein, mouse