ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs

Abstract

SUMMARY 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. We find 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.

Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes

“…Some tumors with equivocal or negative scores expressed ASCL1, suggesting the possibility that they represent NE or neural stem cells. NEUROD1, which has been suggested as an alternative regulator of NE differentiation in a subset of SCLC (10,16), was expressed in a large subset of tumors and cell lines, almost all of them with positive NE scores. However, SCLC cells expressing NEUROD1 usually also expressed ASCL1, making it difficult to assess the relationship of NEUROD1 with NE differentiation.…”

“…In most cases, high NE expression is associated with expression of the master transcription factor ASCL1. In some cases, however, as exemplified by a GEM model and in human tumors and cell lines (11,16,17), the alternative neural transcription factor NEUROD1 is activated, either with or without expression of ASCL1. NEUROD1 expression is associated with varying levels of NE expression, but the low NE subtype usually has loss of both of these master transcription factors.…”

“…Relationship between expression of ASCL1, NEUROD1, ASCL2 and the NE score The basic loop-helix-loop transcription factors ASCL1 and NEUROD1, both of which play important roles in regulating expression of NE properties (16). We therefore correlated the expression of ASCL1 and NEUROD1 in tumors and cell lines ( Figure 6, upper panel).…”

“…Most of the information is from the references cited, although some data are presented in this report. In some reports the variant term is used, while in others it is inferred from the description of the SCLC cells More frequent in tumors recurring after initial response to therapy (5,6) More frequent expression of MYC family gene expression (5,6) and promoted by MYC expression in vivo (11) Altered cellular morphology (5,6) Altered cell line growth characteristics (5,6) Rapid growth and increased cloning efficiencies (5,6,11) Increased resistance to radiation exposure (7) Increased sensitivity to Seneca Valley virus (10) Frequent partial or complete loss of NE cell properties (5,6) HRAS transfection selectively induces altered (variant) morphology in SCLC cell line (13) Classic and variant cell lines vary in expression of extracellular matrix proteins (14) Classic and variant cell lines differ in their responses to retinoic acid (15) Expression of REST gene, an inhibitor of neural and NE properties (this report and 48) in cells that have lost NE properties Often associated with loss of ASCL1 master transcription factor and expression of NEUROD1 master transcription factor or loss of both transcription factors (11,16) Transl Lung Cancer Res 2018;7(1):32-49 tlcr.amegroups.com associated with alterations in the expression of the master transcription regulator ASCL1, a member of the basic helix-loop-helix (BHLH) family of transcription factors. The major purpose of this manuscript is to document the heterogeneity of SCLC, with respect to morphology, growth characteristics, other biological properties and the complex relationship of NE differentiation with respect to ASCL1, the Notch pathway and other inhibitors and promoters of NE differentiation.…”

Primary lung cancer with metastasis to the ipsilateral breast-a case report

“…Small cell lung cancer (SCLC) presents as a highly aggressive malignant disease that displays poorly differentiated neuroendocrine features. 18 Nearly all cases of SCLC are attributable to cigarette smoking, accounting for 15% of all cases. In the UK, lung cancer is the third (13%) most commonly diagnosed cancer after breast (15%) and prostate (13%) and before bowel cancer (11%).…”