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

Yu Han Huang, Olaf Klingbeil, Xue Yan He, Xiaoli S. Wu, Gayatri Arun, Bin Lu, Tim D.D. Somerville, Joseph P. Milazzo, John E. Wilkinson, Osama E. Demerdash, David L. Spector, Mikala Egeblad, Junwei Shi, Christopher R. Vakoc

Research output: Contribution to journalArticlepeer-review

233 Scopus citations

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.

Original languageEnglish
Pages (from-to)915-928
Number of pages14
JournalGenes and Development
Volume32
Issue number13-14
DOIs
StatePublished - Jul 1 2018

Keywords

  • Enhancer
  • Master regulator
  • POU2F3
  • Small cell lung cancer
  • Tuft cell

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