POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer

Huang, Y. H., Klingbeil, O., He, X. Y., Wu, X. S., Arun, G., Lu, B., Somerville, T. D. D., Milazzo, J. P., Wilkinson, J. E., Demerdash, O. E., Spector, D. L., Egeblad, M., Shi, J., Vakoc, C. R. (July 2018) POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes Dev, 32 (13-14). pp. 915-928. ISSN 0890-9369

URL: https://www.ncbi.nlm.nih.gov/pubmed/29945888
DOI: 10.1101/gad.314815.118

Abstract

Small cell lung cancer (SCLC) is widely considered to be a tumor of pulmonary neuroendocrine cells; however, a variant form of this disease has been described that lacks neuroendocrine features. Here, we applied domain-focused CRISPR screening to human cancer cell lines to identify the transcription factor (TF) POU2F3 (POU class 2 homeobox 3; also known as SKN-1a/OCT-11) as a powerful dependency in a subset of SCLC lines. An analysis of human SCLC specimens revealed that POU2F3 is expressed exclusively in variant SCLC tumors that lack expression of neuroendocrine markers and instead express markers of a chemosensory lineage known as tuft cells. Using chromatin- and RNA-profiling experiments, we provide evidence that POU2F3 is a master regulator of tuft cell identity in a variant form of SCLC. Moreover, we show that most SCLC tumors can be classified into one of three lineages based on the expression of POU2F3, ASCL1, or NEUROD1. Our CRISPR screens exposed other unique dependencies in POU2F3-expressing SCLC lines, including the lineage TFs SOX9 and ASCL2 and the receptor tyrosine kinase IGF1R (insulin-like growth factor 1 receptor). These data reveal POU2F3 as a cell identity determinant and a dependency in a tuft cell-like variant of SCLC, which may reflect a previously unrecognized cell of origin or a trans-differentiation event in this disease.

Item Type: Paper
Uncontrolled Keywords: Pou2f3 enhancer master regulator small cell lung cancer tuft cell
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation

diseases & disorders > cancer > cancer types > lung cancer
CSHL Authors:
Communities: CSHL labs > Egeblad lab
CSHL labs > Spector lab
CSHL labs > Vakoc lab
Depositing User: Matt Covey
Date: 1 July 2018
Date Deposited: 23 Jul 2018 18:55
Last Modified: 23 Jul 2018 18:55
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36979

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