Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer

Daniel J. McGrail; Jeannine Garnett; Jun Yin; Hui Dai; David J.H. Shih; Truong Nguyen Anh Lam; Yang Li; Chaoyang Sun; Yongsheng Li; Rosemarie Schmandt; Ji Yuan Wu; Limei Hu; Yulong Liang; Guang Peng; Eric Jonasch; David Menter; Melinda S. Yates; Scott Kopetz; Karen H. Lu; Russell Broaddus; Gordon B. Mills; Nidhi Sahni; Shiaw Yih Lin

doi:10.1016/j.ccell.2020.01.011

Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer

Daniel J. McGrail, Jeannine Garnett, Jun Yin, Hui Dai, David J.H. Shih, Truong Nguyen Anh Lam, Yang Li, Chaoyang Sun, Yongsheng Li, Rosemarie Schmandt, Ji Yuan Wu, Limei Hu, Yulong Liang, Guang Peng, Eric Jonasch, David Menter, Melinda S. Yates, Scott Kopetz, Karen H. Lu, Russell BroaddusGordon B. Mills, Nidhi Sahni, Shiaw Yih Lin

Cell Developmental and Cancer Biology

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

56 Scopus citations

Abstract

McGrail et al. find that the abundance of destabilizing mutations in microsatellite unstable (MSI) tumors causes proteome instability and accumulation of misfolded proteins. To compensate, MSI tumors rely on a Nedd8-mediated pathway to clear misfolded aggregates, which can be therapeutically targeted by MLN4924.

Original language	English (US)
Pages (from-to)	371-386.e12
Journal	Cancer Cell
Volume	37
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2020.01.011
State	Published - Mar 16 2020

Keywords

colorectal cancer (COAD)
endometrial cancer (UCEC)
immunotherapy
microsatellite instability (MSI)
mismatch repair (MMR)
neddylation
protein degredation
protein homeostasis

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2020.01.011

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McGrail, D. J., Garnett, J., Yin, J., Dai, H., Shih, D. J. H., Lam, T. N. A., Li, Y., Sun, C., Li, Y., Schmandt, R., Wu, J. Y., Hu, L., Liang, Y., Peng, G., Jonasch, E., Menter, D., Yates, M. S., Kopetz, S., Lu, K. H., ... Lin, S. Y. (2020). Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer. Cancer Cell, 37(3), 371-386.e12. https://doi.org/10.1016/j.ccell.2020.01.011

McGrail, DJ, Garnett, J, Yin, J, Dai, H, Shih, DJH, Lam, TNA, Li, Y, Sun, C, Li, Y, Schmandt, R, Wu, JY, Hu, L, Liang, Y, Peng, G, Jonasch, E, Menter, D, Yates, MS, Kopetz, S, Lu, KH, Broaddus, R, Mills, GB, Sahni, N & Lin, SY 2020, 'Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer', Cancer Cell, vol. 37, no. 3, pp. 371-386.e12. https://doi.org/10.1016/j.ccell.2020.01.011

@article{34cae294339d401184153842d03233c3,

title = "Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer",

abstract = "McGrail et al. find that the abundance of destabilizing mutations in microsatellite unstable (MSI) tumors causes proteome instability and accumulation of misfolded proteins. To compensate, MSI tumors rely on a Nedd8-mediated pathway to clear misfolded aggregates, which can be therapeutically targeted by MLN4924.",

keywords = "colorectal cancer (COAD), endometrial cancer (UCEC), immunotherapy, microsatellite instability (MSI), mismatch repair (MMR), neddylation, protein degredation, protein homeostasis",

author = "McGrail, {Daniel J.} and Jeannine Garnett and Jun Yin and Hui Dai and Shih, {David J.H.} and Lam, {Truong Nguyen Anh} and Yang Li and Chaoyang Sun and Yongsheng Li and Rosemarie Schmandt and Wu, {Ji Yuan} and Limei Hu and Yulong Liang and Guang Peng and Eric Jonasch and David Menter and Yates, {Melinda S.} and Scott Kopetz and Lu, {Karen H.} and Russell Broaddus and Mills, {Gordon B.} and Nidhi Sahni and Lin, {Shiaw Yih}",

note = "Funding Information: Funding was provided by NCI grant T32CA186892 to D.J.M., NCI grant R01 CA218287 to S.-Y.L., a Developmental Research Program grant to S.-Y.L. under the MD Anderson Uterine Cancer Specialized Programs of Research Excellence ( SPORE ) in Uterine Cancer (NCI grant P50CA098258 , PIs K.H.L. and R.B.), D.J.H.S. is supported by a training fellowship from the Gulf Coast Consortia, on the Computational Cancer Biology Training Program ( CPRIT grant no. RP170593 ), N.S. is a CPRIT Scholar in Cancer Research with funding from the Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator Grant RR160021 and Alfred P. Sloan Research Fellowship FG-2018-10,723 , as well as NCI grant U01CA217842 (PI G.B.M.). Funding to M.S.Y. was provided by NCI grant R01 CA216103 and the Roberta Detz Endometrial Cancer Research grant from the Foundation for Women's Cancer . We thank Yiling Lu, MD, for ensuring that the cell lines used in this publication were appropriately authenticated and mycoplasma-free, Guo-Min Li, PhD, UT Southwestern, for providing us with the bacteriophages used in the MMR functional assays, and Briana Dennehey, PhD, for critically reading and editing the manuscript. We are grateful to many MD Anderson Cancer Center core facilities funded by grant NCI grant CA016672 : the Functional Genomics Core (shRNA and ORFeome Core) for reagents and technical assistance, the Characterized Cell Line Core for STR DNA fingerprinting, the Sequencing and Microarray Facility for transcriptome analysis, the High Throughput Genotyping Core for scanning Illumina BeadChips, the CRISPR Core for cell-line generation, and the Research Animal Support Facility. The results here are in whole or part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/ . Funding Information: Funding was provided by NCI grant T32CA186892 to D.J.M. NCI grant R01 CA218287 to S.-Y.L. a Developmental Research Program grant to S.-Y.L. under the MD Anderson Uterine Cancer Specialized Programs of Research Excellence (SPORE) in Uterine Cancer (NCI grant P50CA098258, PIs K.H.L. and R.B.), D.J.H.S. is supported by a training fellowship from the Gulf Coast Consortia, on the Computational Cancer Biology Training Program (CPRIT grant no. RP170593), N.S. is a CPRIT Scholar in Cancer Research with funding from the Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator Grant RR160021 and Alfred P. Sloan Research Fellowship FG-2018-10,723, as well as NCI grant U01CA217842 (PI G.B.M.). Funding to M.S.Y. was provided by NCI grant R01 CA216103 and the Roberta Detz Endometrial Cancer Research grant from the Foundation for Women's Cancer. We thank Yiling Lu, MD, for ensuring that the cell lines used in this publication were appropriately authenticated and mycoplasma-free, Guo-Min Li, PhD, UT Southwestern, for providing us with the bacteriophages used in the MMR functional assays, and Briana Dennehey, PhD, for critically reading and editing the manuscript. We are grateful to many MD Anderson Cancer Center core facilities funded by grant NCI grant CA016672: the Functional Genomics Core (shRNA and ORFeome Core) for reagents and technical assistance, the Characterized Cell Line Core for STR DNA fingerprinting, the Sequencing and Microarray Facility for transcriptome analysis, the High Throughput Genotyping Core for scanning Illumina BeadChips, the CRISPR Core for cell-line generation, and the Research Animal Support Facility. The results here are in whole or part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. D.J.M. J.G. N.S. and S.-Y.L. conceived the study. D.J.M. wrote the manuscript with significant input from N.S. and S.-Y.L. D.J.M. performed computational analysis including generation and validation of the dMMR signature, drug sensitivity prediction and cross-validation, mutant protein modeling, protein binding analysis, and multispectral image analysis, as well as experimental analysis of whole proteome and mutant protein stability, misfolded protein clearance and other fractionation assays, ICD, immunofluorescence microscopy, flow cytometry, and denaturing immunoprecipitations, and contributed to animal studies. J.G. generated and functionally verified dMMR cell lines, tested drugs, performed transcriptome profiling and qRT-PCR, analyzed cytokine production, and contributed to animal studies. N.S. Yongsheng Li, and L.H. generated the allele libraries. N.S. contributed to protein modeling and mutant protein binding analysis. J.Y. Yang Li, C.S. and Yulong Liang performed animal studies. H.D. generated cell lines, tested drug sensitivity, performed western blot analysis, contributed to various in vitro experiments, and performed animal studies. D.J.H.S. performed mutation simulations and whole-exome sequencing. T.N.A.L. performed multispectral immunofluorescence and was overseen by E.J. R.S. M.S.Y. K.L. and R.B. generated the targeted Msh2 deletion mouse model and developed the associated cell lines. J.Y.W. D.M. and S.K. generated PDXs. G.P. developed cell lines. R.B. provided patient samples. R.B. S.K. and G.B.M. provided intellectual input throughout the course of the study. All authors read and approved the final manuscript. G.B.M. consults with AstraZeneca, ImmunoMET, Ionis, Nuevolution, PDX bio, Signalchem, Symphogen, and Tarveda, has stock options with Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindle Top Ventures, and Tarveda, sponsored research from AstraZeneca, Immunomet, Pfizer, Nanostring, and Tesaro, travel support from Chrysallis Bio, and has licensed technology to Nanostring and Myriad Genetics. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = mar,

day = "16",

doi = "10.1016/j.ccell.2020.01.011",

language = "English (US)",

volume = "37",

pages = "371--386.e12",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer

AU - McGrail, Daniel J.

AU - Garnett, Jeannine

AU - Yin, Jun

AU - Dai, Hui

AU - Shih, David J.H.

AU - Lam, Truong Nguyen Anh

AU - Li, Yang

AU - Sun, Chaoyang

AU - Li, Yongsheng

AU - Schmandt, Rosemarie

AU - Wu, Ji Yuan

AU - Hu, Limei

AU - Liang, Yulong

AU - Peng, Guang

AU - Jonasch, Eric

AU - Menter, David

AU - Yates, Melinda S.

AU - Kopetz, Scott

AU - Lu, Karen H.

AU - Broaddus, Russell

AU - Mills, Gordon B.

AU - Sahni, Nidhi

AU - Lin, Shiaw Yih

N1 - Funding Information: Funding was provided by NCI grant T32CA186892 to D.J.M., NCI grant R01 CA218287 to S.-Y.L., a Developmental Research Program grant to S.-Y.L. under the MD Anderson Uterine Cancer Specialized Programs of Research Excellence ( SPORE ) in Uterine Cancer (NCI grant P50CA098258 , PIs K.H.L. and R.B.), D.J.H.S. is supported by a training fellowship from the Gulf Coast Consortia, on the Computational Cancer Biology Training Program ( CPRIT grant no. RP170593 ), N.S. is a CPRIT Scholar in Cancer Research with funding from the Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator Grant RR160021 and Alfred P. Sloan Research Fellowship FG-2018-10,723 , as well as NCI grant U01CA217842 (PI G.B.M.). Funding to M.S.Y. was provided by NCI grant R01 CA216103 and the Roberta Detz Endometrial Cancer Research grant from the Foundation for Women's Cancer . We thank Yiling Lu, MD, for ensuring that the cell lines used in this publication were appropriately authenticated and mycoplasma-free, Guo-Min Li, PhD, UT Southwestern, for providing us with the bacteriophages used in the MMR functional assays, and Briana Dennehey, PhD, for critically reading and editing the manuscript. We are grateful to many MD Anderson Cancer Center core facilities funded by grant NCI grant CA016672 : the Functional Genomics Core (shRNA and ORFeome Core) for reagents and technical assistance, the Characterized Cell Line Core for STR DNA fingerprinting, the Sequencing and Microarray Facility for transcriptome analysis, the High Throughput Genotyping Core for scanning Illumina BeadChips, the CRISPR Core for cell-line generation, and the Research Animal Support Facility. The results here are in whole or part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/ . Funding Information: Funding was provided by NCI grant T32CA186892 to D.J.M. NCI grant R01 CA218287 to S.-Y.L. a Developmental Research Program grant to S.-Y.L. under the MD Anderson Uterine Cancer Specialized Programs of Research Excellence (SPORE) in Uterine Cancer (NCI grant P50CA098258, PIs K.H.L. and R.B.), D.J.H.S. is supported by a training fellowship from the Gulf Coast Consortia, on the Computational Cancer Biology Training Program (CPRIT grant no. RP170593), N.S. is a CPRIT Scholar in Cancer Research with funding from the Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator Grant RR160021 and Alfred P. Sloan Research Fellowship FG-2018-10,723, as well as NCI grant U01CA217842 (PI G.B.M.). Funding to M.S.Y. was provided by NCI grant R01 CA216103 and the Roberta Detz Endometrial Cancer Research grant from the Foundation for Women's Cancer. We thank Yiling Lu, MD, for ensuring that the cell lines used in this publication were appropriately authenticated and mycoplasma-free, Guo-Min Li, PhD, UT Southwestern, for providing us with the bacteriophages used in the MMR functional assays, and Briana Dennehey, PhD, for critically reading and editing the manuscript. We are grateful to many MD Anderson Cancer Center core facilities funded by grant NCI grant CA016672: the Functional Genomics Core (shRNA and ORFeome Core) for reagents and technical assistance, the Characterized Cell Line Core for STR DNA fingerprinting, the Sequencing and Microarray Facility for transcriptome analysis, the High Throughput Genotyping Core for scanning Illumina BeadChips, the CRISPR Core for cell-line generation, and the Research Animal Support Facility. The results here are in whole or part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. D.J.M. J.G. N.S. and S.-Y.L. conceived the study. D.J.M. wrote the manuscript with significant input from N.S. and S.-Y.L. D.J.M. performed computational analysis including generation and validation of the dMMR signature, drug sensitivity prediction and cross-validation, mutant protein modeling, protein binding analysis, and multispectral image analysis, as well as experimental analysis of whole proteome and mutant protein stability, misfolded protein clearance and other fractionation assays, ICD, immunofluorescence microscopy, flow cytometry, and denaturing immunoprecipitations, and contributed to animal studies. J.G. generated and functionally verified dMMR cell lines, tested drugs, performed transcriptome profiling and qRT-PCR, analyzed cytokine production, and contributed to animal studies. N.S. Yongsheng Li, and L.H. generated the allele libraries. N.S. contributed to protein modeling and mutant protein binding analysis. J.Y. Yang Li, C.S. and Yulong Liang performed animal studies. H.D. generated cell lines, tested drug sensitivity, performed western blot analysis, contributed to various in vitro experiments, and performed animal studies. D.J.H.S. performed mutation simulations and whole-exome sequencing. T.N.A.L. performed multispectral immunofluorescence and was overseen by E.J. R.S. M.S.Y. K.L. and R.B. generated the targeted Msh2 deletion mouse model and developed the associated cell lines. J.Y.W. D.M. and S.K. generated PDXs. G.P. developed cell lines. R.B. provided patient samples. R.B. S.K. and G.B.M. provided intellectual input throughout the course of the study. All authors read and approved the final manuscript. G.B.M. consults with AstraZeneca, ImmunoMET, Ionis, Nuevolution, PDX bio, Signalchem, Symphogen, and Tarveda, has stock options with Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindle Top Ventures, and Tarveda, sponsored research from AstraZeneca, Immunomet, Pfizer, Nanostring, and Tesaro, travel support from Chrysallis Bio, and has licensed technology to Nanostring and Myriad Genetics. The other authors declare no competing interests. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/3/16

Y1 - 2020/3/16

N2 - McGrail et al. find that the abundance of destabilizing mutations in microsatellite unstable (MSI) tumors causes proteome instability and accumulation of misfolded proteins. To compensate, MSI tumors rely on a Nedd8-mediated pathway to clear misfolded aggregates, which can be therapeutically targeted by MLN4924.

AB - McGrail et al. find that the abundance of destabilizing mutations in microsatellite unstable (MSI) tumors causes proteome instability and accumulation of misfolded proteins. To compensate, MSI tumors rely on a Nedd8-mediated pathway to clear misfolded aggregates, which can be therapeutically targeted by MLN4924.

KW - colorectal cancer (COAD)

KW - endometrial cancer (UCEC)

KW - immunotherapy

KW - microsatellite instability (MSI)

KW - mismatch repair (MMR)

KW - neddylation

KW - protein degredation

KW - protein homeostasis

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DO - 10.1016/j.ccell.2020.01.011

M3 - Article

C2 - 32109374

AN - SCOPUS:85081226123

SN - 1535-6108

VL - 37

SP - 371-386.e12

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer

Abstract

Keywords

ASJC Scopus subject areas

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