A proteogenomic portrait of lung squamous cell carcinoma

Shankha Satpathy; Karsten Krug; Pierre M Jean Beltran; Sara R Savage; Francesca Petralia; Chandan Kumar-Sinha; Yongchao Dou; Boris Reva; M Harry Kane; Shayan C Avanessian; Suhas V Vasaikar; Azra Krek; Jonathan T Lei; Eric J Jaehnig; Tatiana Omelchenko; Yifat Geffen; Erik J Bergstrom; Vasileios Stathias; Karen E Christianson; David I Heiman; Marcin P Cieslik; Song Cao; Xiaoyu Song; Jiayi Ji; Wenke Liu; Kai Li; Bo Wen; Yize Li; Zeynep H Gümüş; Myvizhi Esai Selvan; Rama Soundararajan; Tanvi H Visal; Maria G Raso; Edwin Roger Parra; Özgün Babur; Pankaj Vats; Shankara Anand; Tobias Schraink; MacIntosh Cornwell; Fernanda Martins Rodrigues; Houxiang Zhu; Chia-Kuei Mo; Yuping Zhang; Felipe da Veiga Leprevost; Chen Huang; Arul M Chinnaiyan; Matthew A Wyczalkowski; Gilbert S Omenn; Chelsea J Newton; Stephan Schurer; Kelly V Ruggles; David Fenyö; Scott D Jewell; Mathangi Thiagarajan; Mehdi Mesri; Henry Rodriguez; Sendurai A Mani; Namrata D Udeshi; Gad Getz; James Suh; Qing Kay Li; Galen Hostetter; Paul K Paik; Saravana M Dhanasekaran; Ramaswamy Govindan; Li Ding; Ana I Robles; Karl R Clauser; Alexey I Nesvizhskii; Pei Wang; Steven A Carr; Bing Zhang; D R Mani; Michael A Gillette; Clinical Proteomic Tumor Analysis Consortium

doi:10.1016/j.cell.2021.07.016

A proteogenomic portrait of lung squamous cell carcinoma

Cell. 2021 Aug 5;184(16):4348-4371.e40. doi: 10.1016/j.cell.2021.07.016.

Authors

Shankha Satpathy¹, Karsten Krug², Pierre M Jean Beltran², Sara R Savage³, Francesca Petralia⁴, Chandan Kumar-Sinha⁵, Yongchao Dou³, Boris Reva⁴, M Harry Kane², Shayan C Avanessian², Suhas V Vasaikar⁶, Azra Krek⁴, Jonathan T Lei³, Eric J Jaehnig³, Tatiana Omelchenko⁷, Yifat Geffen², Erik J Bergstrom², Vasileios Stathias⁸, Karen E Christianson², David I Heiman², Marcin P Cieslik⁹, Song Cao¹⁰, Xiaoyu Song¹¹, Jiayi Ji¹¹, Wenke Liu¹², Kai Li³, Bo Wen³, Yize Li¹⁰, Zeynep H Gümüş⁴, Myvizhi Esai Selvan⁴, Rama Soundararajan⁶, Tanvi H Visal⁶, Maria G Raso⁶, Edwin Roger Parra⁶, Özgün Babur¹³, Pankaj Vats⁵, Shankara Anand², Tobias Schraink¹⁴, MacIntosh Cornwell¹⁴, Fernanda Martins Rodrigues¹⁰, Houxiang Zhu¹⁰, Chia-Kuei Mo¹⁰, Yuping Zhang⁵, Felipe da Veiga Leprevost⁵, Chen Huang³, Arul M Chinnaiyan⁵, Matthew A Wyczalkowski¹⁰, Gilbert S Omenn¹⁵, Chelsea J Newton¹⁶, Stephan Schurer⁸, Kelly V Ruggles¹⁴, David Fenyö¹², Scott D Jewell¹⁶, Mathangi Thiagarajan¹⁷, Mehdi Mesri¹⁸, Henry Rodriguez¹⁸, Sendurai A Mani⁶, Namrata D Udeshi², Gad Getz², James Suh¹⁷, Qing Kay Li¹⁹, Galen Hostetter¹⁶, Paul K Paik⁷, Saravana M Dhanasekaran⁵, Ramaswamy Govindan¹⁰, Li Ding¹⁰, Ana I Robles¹⁸, Karl R Clauser², Alexey I Nesvizhskii⁹, Pei Wang⁴, Steven A Carr²⁰, Bing Zhang²¹, D R Mani²², Michael A Gillette²³; Clinical Proteomic Tumor Analysis Consortium

Collaborators

Clinical Proteomic Tumor Analysis Consortium:
Alex Green, Alfredo Molinolo, Alicia Francis, Amanda G Paulovich, Andrii Karnuta, Antonio Colaprico, Barbara Hindenach, Barbara L Pruetz, Bartosz Kubisa, Brian J Druker, Carissa Huynh, Charles A Goldthwaite Jr, Chet Birger, Christopher R Kinsinger, Corbin D Jones, Dan Rohrer, Dana R Valley, Daniel W Chan, David Chesla, Donna Hansel, Elena V Ponomareva, Elizabeth Duffy, Eric Burks, Eric E Schadt, Eugene S Fedorov, Eunkyung An, Fei Ding, George D Wilson, Harsh Batra, Hui Zhang, Jennifer E Maas, Jennifer Eschbacher, Karen A Ketchum, Karin D Rodland, Katherine A Hoadley, Kei Suzuki, Ki Sung Um, Liqun Qi, Lori Bernard, Maciej Wiznerowicz, Małgorzata Wojtyś, Marcin J Domagalski, Matthew J Ellis, Maureen A Dyer, Melissa Borucki, Meenakshi Anurag, Michael J Birrer, Midie Xu, Mikhail Krotevich, Nancy Roche, Nathan J Edwards, Negin Vatanian, Neil R Mucci, Nicollette Maunganidze, Nikolay Gabrovski, Olga Potapova, Oluwole Fadare, Pamela Grady, Peter B McGarvey, Pushpa Hariharan, Ratna R Thangudu, Rebecca Montgomery, Renganayaki Pandurengan, Richard D Smith, Robert J Welsh, Sailaja Mareedu, Samuel H Payne, Sandra Cottingham, Shilpi Singh, Shirley X Tsang, Shuang Cai, Stacey Gabriel, Tao Liu, Tara Hiltke, Tanmayi Vashist, Thomas Bauer, Volodymyr Sovenko, Warren G Tourtellotte, Weiping Ma, William Bocik, Wohaib Hasan, Xiaojun Jing, Ximing Tang, Yuxing Liao, Yvonne, Shutack, Zhen Zhang, Ziad Hanhan

Affiliations

¹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: shankha@broadinstitute.org.
² Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
³ Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁵ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁸ Sylvester Comprehensive Cancer Center and Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
⁹ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁰ Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA.
¹¹ Department of Population Health Science and Policy, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹² Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.
¹³ Computer Science Department, University of Massachusetts Boston, Boston, MA 02125, USA.
¹⁴ Institute for Systems Genetics and Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA.
¹⁵ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁶ Van Andel Research Institute, Grand Rapids, MI 49503, USA.
¹⁷ Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
¹⁸ Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA.
¹⁹ Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA.
²⁰ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: scarr@broad.mit.edu.
²¹ Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: bing.zhang@bcm.edu.
²² Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: manidr@broadinstitute.org.
²³ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02115, USA. Electronic address: gillette@broadinstitute.org.

Abstract

Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.

Keywords: CPTAC; acetylation; genomics; lung cancer; phosphorylation; protein; proteogenomics; proteomics; squamous; ubiquitylation.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Acetylation
Adult
Aged
Aged, 80 and over
Carcinoma, Squamous Cell / genetics*
Cluster Analysis
Cyclin-Dependent Kinase 4 / genetics
Cyclin-Dependent Kinase 6 / genetics
Epithelial-Mesenchymal Transition / genetics
Female
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms / genetics*
Male
Middle Aged
Mutation / genetics
Neoplasm Proteins / metabolism
Phosphorylation
Protein Binding
Proteogenomics*
Receptor Tyrosine Kinase-like Orphan Receptors / metabolism
Receptors, Platelet-Derived Growth Factor / metabolism
Signal Transduction
Ubiquitination

Substances

Neoplasm Proteins
ROR2 protein, human
Receptor Tyrosine Kinase-like Orphan Receptors
Receptors, Platelet-Derived Growth Factor
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6

Abstract

Publication types

MeSH terms

Substances

Grants and funding