An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis

Suzie K. Hight, Allison Mootz, Rahul K. Kollipara, Elizabeth McMillan, Paul Yenerall, Yoichi Otaki, Long Shan Li, Kimberley Avila, Michael Peyton, Jaime Rodriguez-Canales, Barbara Mino, Pamela Villalobos, Luc Girard, Patrick Dospoy, Jill Larsen, Michael A. White, John V. Heymach, Ignacio I. Wistuba, Ralf Kittler, John D. Minna

Research output: Contribution to journalArticle

Abstract

Using a mini-library of 1062 lentiviral shRNAs targeting 40 nuclear hormone receptors and 70 of their co-regulators, we searched for potential therapeutic targets that would be important during in vivo tumor growth using a parallel in vitro and in vivo shRNA screening strategy in the non-small cell lung cancer (NSCLC) line NCI-H1819. We identified 21 genes essential for in vitro growth, and nine genes specifically required for tumor survival in vivo, but not in vitro: NCOR2, FOXA1, HDAC1, RXRA, RORB, RARB, MTA2, ETV4, and NR1H2. We focused on FOXA1, since it lies within the most frequently amplified genomic region in lung adenocarcinomas. We found that 14q-amplification in NSCLC cell lines was a biomarker for FOXA1 dependency for both in vivo xenograft growth and colony formation, but not mass culture growth in vitro. FOXA1 knockdown identified genes involved in electron transport among the most differentially regulated, indicating FOXA1 loss may lead to a decrease in cellular respiration. In support of this, FOXA1 amplification was correlated with increased sensitivity to the complex I inhibitor phenformin. Integrative ChipSeq analyses reveal that FOXA1 functions in this genetic context may be at least partially independent of NKX2-1. Our findings are consistent with a neomorphic function for amplified FOXA1, driving an oncogenic transcriptional program. These data provide new insight into the functional consequences of FOXA1 amplification in lung adenocarcinomas, and identify new transcriptional networks for exploration of therapeutic vulnerabilities in this patient population.

Original languageEnglish (US)
Pages (from-to)294-310
Number of pages17
JournalNeoplasia (United States)
Volume22
Issue number8
DOIs
StatePublished - Aug 2020

Keywords

  • FOXA1
  • NKX2-1
  • Non-small cell lung cancer
  • Pooled shRNA screens
  • Xenograft

ASJC Scopus subject areas

  • Cancer Research

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    Hight, S. K., Mootz, A., Kollipara, R. K., McMillan, E., Yenerall, P., Otaki, Y., Li, L. S., Avila, K., Peyton, M., Rodriguez-Canales, J., Mino, B., Villalobos, P., Girard, L., Dospoy, P., Larsen, J., White, M. A., Heymach, J. V., Wistuba, I. I., Kittler, R., & Minna, J. D. (2020). An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis. Neoplasia (United States), 22(8), 294-310. https://doi.org/10.1016/j.neo.2020.04.005