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Genes Dev. 2018 Jul 1;32(13-14):915-928. doi: 10.1101/gad.314815.118. Epub 2018 Jun 26.

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

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Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Genetics Program, Stony Brook University, Stony Brook, New York 11794, USA.
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.


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.


POU2F3; enhancer; master regulator; small cell lung cancer; tuft cell

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