MAX Functions as a Tumor Suppressor and Rewires Metabolism in Small Cell Lung Cancer

Arnaud Augert; Haritha Mathsyaraja; Ali H. Ibrahim; Brian Freie; Michael J. Geuenich; Pei Feng Cheng; Sydney P. Alibeckoff; Nan Wu; Joseph B. Hiatt; Ryan Basom; Adi Gazdar; Lucas B. Sullivan; Robert N. Eisenman; David MacPherson

doi:10.1016/j.ccell.2020.04.016

MAX Functions as a Tumor Suppressor and Rewires Metabolism in Small Cell Lung Cancer

Arnaud Augert, Haritha Mathsyaraja, Ali H. Ibrahim, Brian Freie, Michael J. Geuenich, Pei Feng Cheng, Sydney P. Alibeckoff, Nan Wu, Joseph B. Hiatt, Ryan Basom, Adi Gazdar, Lucas B. Sullivan, Robert N. Eisenman, David MacPherson

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

Abstract

Small cell lung cancer (SCLC) is a highly aggressive and lethal neoplasm. To identify candidate tumor suppressors we applied CRISPR/Cas9 gene inactivation screens to a cellular model of early-stage SCLC. Among the top hits was MAX, the obligate heterodimerization partner for MYC family proteins that is mutated in human SCLC. Max deletion increases growth and transformation in cells and dramatically accelerates SCLC progression in an Rb1/Trp53-deleted mouse model. In contrast, deletion of Max abrogates tumorigenesis in MYCL-overexpressing SCLC. Max deletion in SCLC resulted in derepression of metabolic genes involved in serine and one-carbon metabolism. By increasing serine biosynthesis, Max-deleted cells exhibit resistance to serine depletion. Thus, Max loss results in metabolic rewiring and context-specific tumor suppression.

Original language	English (US)
Pages (from-to)	97-114.e7
Journal	Cancer cell
Volume	38
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2020.04.016
State	Published - Jul 13 2020
Externally published	Yes

Keywords

cancer
CRISPR-Cas9 genetic screens
MAX
mouse model
MYC
SCLC
serine and one-carbon metabolism
small cell lung cancer
Transcriptional regulation
tumor suppressor genes

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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Augert, A., Mathsyaraja, H., Ibrahim, A. H., Freie, B., Geuenich, M. J., Cheng, P. F., Alibeckoff, S. P., Wu, N., Hiatt, J. B., Basom, R., Gazdar, A., Sullivan, L. B., Eisenman, R. N., & MacPherson, D. (2020). MAX Functions as a Tumor Suppressor and Rewires Metabolism in Small Cell Lung Cancer. Cancer cell, 38(1), 97-114.e7. https://doi.org/10.1016/j.ccell.2020.04.016

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abstract = "Small cell lung cancer (SCLC) is a highly aggressive and lethal neoplasm. To identify candidate tumor suppressors we applied CRISPR/Cas9 gene inactivation screens to a cellular model of early-stage SCLC. Among the top hits was MAX, the obligate heterodimerization partner for MYC family proteins that is mutated in human SCLC. Max deletion increases growth and transformation in cells and dramatically accelerates SCLC progression in an Rb1/Trp53-deleted mouse model. In contrast, deletion of Max abrogates tumorigenesis in MYCL-overexpressing SCLC. Max deletion in SCLC resulted in derepression of metabolic genes involved in serine and one-carbon metabolism. By increasing serine biosynthesis, Max-deleted cells exhibit resistance to serine depletion. Thus, Max loss results in metabolic rewiring and context-specific tumor suppression.",

keywords = "cancer, CRISPR-Cas9 genetic screens, MAX, mouse model, MYC, SCLC, serine and one-carbon metabolism, small cell lung cancer, Transcriptional regulation, tumor suppressor genes",

author = "Arnaud Augert and Haritha Mathsyaraja and Ibrahim, {Ali H.} and Brian Freie and Geuenich, {Michael J.} and Cheng, {Pei Feng} and Alibeckoff, {Sydney P.} and Nan Wu and Hiatt, {Joseph B.} and Ryan Basom and Adi Gazdar and Sullivan, {Lucas B.} and Eisenman, {Robert N.} and David MacPherson",

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doi = "10.1016/j.ccell.2020.04.016",

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AU - Geuenich, Michael J.

AU - Cheng, Pei Feng

AU - Alibeckoff, Sydney P.

AU - Wu, Nan

AU - Hiatt, Joseph B.

AU - Basom, Ryan

AU - Gazdar, Adi

AU - Sullivan, Lucas B.

AU - Eisenman, Robert N.

AU - MacPherson, David

PY - 2020/7/13

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N2 - Small cell lung cancer (SCLC) is a highly aggressive and lethal neoplasm. To identify candidate tumor suppressors we applied CRISPR/Cas9 gene inactivation screens to a cellular model of early-stage SCLC. Among the top hits was MAX, the obligate heterodimerization partner for MYC family proteins that is mutated in human SCLC. Max deletion increases growth and transformation in cells and dramatically accelerates SCLC progression in an Rb1/Trp53-deleted mouse model. In contrast, deletion of Max abrogates tumorigenesis in MYCL-overexpressing SCLC. Max deletion in SCLC resulted in derepression of metabolic genes involved in serine and one-carbon metabolism. By increasing serine biosynthesis, Max-deleted cells exhibit resistance to serine depletion. Thus, Max loss results in metabolic rewiring and context-specific tumor suppression.

AB - Small cell lung cancer (SCLC) is a highly aggressive and lethal neoplasm. To identify candidate tumor suppressors we applied CRISPR/Cas9 gene inactivation screens to a cellular model of early-stage SCLC. Among the top hits was MAX, the obligate heterodimerization partner for MYC family proteins that is mutated in human SCLC. Max deletion increases growth and transformation in cells and dramatically accelerates SCLC progression in an Rb1/Trp53-deleted mouse model. In contrast, deletion of Max abrogates tumorigenesis in MYCL-overexpressing SCLC. Max deletion in SCLC resulted in derepression of metabolic genes involved in serine and one-carbon metabolism. By increasing serine biosynthesis, Max-deleted cells exhibit resistance to serine depletion. Thus, Max loss results in metabolic rewiring and context-specific tumor suppression.

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KW - Transcriptional regulation

KW - tumor suppressor genes

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MAX Functions as a Tumor Suppressor and Rewires Metabolism in Small Cell Lung Cancer

Abstract

Keywords

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