An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-08-01
|
| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558620301172 |
| id |
doaj-482fd373bde3424183dc0e497a6a3920 |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis Neoplasia: An International Journal for Oncology Research Non-small cell lung cancer FOXA1 NKX2-1 Pooled shRNA screens Xenograft |
| author_facet |
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 |
| author_sort |
Suzie K. Hight |
| title |
An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis |
| title_short |
An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis |
| title_full |
An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis |
| title_fullStr |
An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis |
| title_full_unstemmed |
An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis |
| title_sort |
in vivo functional genomics screen of nuclear receptors and their co-regulators identifies foxa1 as an essential gene in lung tumorigenesis |
| publisher |
Elsevier |
| series |
Neoplasia: An International Journal for Oncology Research |
| issn |
1476-5586 |
| publishDate |
2020-08-01 |
| description |
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. |
| topic |
Non-small cell lung cancer FOXA1 NKX2-1 Pooled shRNA screens Xenograft |
| url |
http://www.sciencedirect.com/science/article/pii/S1476558620301172 |
| work_keys_str_mv |
AT suziekhight aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT allisonmootz aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT rahulkkollipara aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT elizabethmcmillan aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT paulyenerall aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT yoichiotaki aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT longshanli aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT kimberleyavila aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT michaelpeyton aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT jaimerodriguezcanales aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT barbaramino aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT pamelavillalobos aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT lucgirard aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT patrickdospoy aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT jilllarsen aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT michaelawhite aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT johnvheymach aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT ignacioiwistuba aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT ralfkittler aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT johndminna aninvivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT suziekhight invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT allisonmootz invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT rahulkkollipara invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT elizabethmcmillan invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT paulyenerall invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT yoichiotaki invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT longshanli invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT kimberleyavila invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT michaelpeyton invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT jaimerodriguezcanales invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT barbaramino invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT pamelavillalobos invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT lucgirard invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT patrickdospoy invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT jilllarsen invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT michaelawhite invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT johnvheymach invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT ignacioiwistuba invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT ralfkittler invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis AT johndminna invivofunctionalgenomicsscreenofnuclearreceptorsandtheircoregulatorsidentifiesfoxa1asanessentialgeneinlungtumorigenesis |
| _version_ |
1724494934675816448 |
| spelling |
doaj-482fd373bde3424183dc0e497a6a39202020-11-25T03:49:33ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862020-08-01228294310An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesisSuzie K. Hight0Allison Mootz1Rahul K. Kollipara2Elizabeth McMillan3Paul Yenerall4Yoichi Otaki5Long-Shan Li6Kimberley Avila7Michael Peyton8Jaime Rodriguez-Canales9Barbara Mino10Pamela Villalobos11Luc Girard12Patrick Dospoy13Jill Larsen14Michael A. White15John V. Heymach16Ignacio I. Wistuba17Ralf Kittler18John D. Minna19Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USAHamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USAEugene McDermott Center for Human Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USADepartment of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USAHamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Eugene McDermott Center for Human Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USAHamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, JapanHamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USAHamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USAHamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USADepartment of Translational and Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USADepartment of Translational and Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USADepartment of Translational and Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USAHamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USAHamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USAHamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, AustraliaDepartment of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USADepartment Thoracic and Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USADepartment of Translational and Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USAEugene McDermott Center for Human Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USAHamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Corresponding author at: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390-8593.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.http://www.sciencedirect.com/science/article/pii/S1476558620301172Non-small cell lung cancerFOXA1NKX2-1Pooled shRNA screensXenograft |