Integrative analysis of non-small cell lung cancer patient-derived xenografts identifies distinct proteotypes associated with patient outcomes

Shideh Mirhadi, Shirley Tam, Quan Li, Nadeem Moghal, Nhu-An Pham, Jiefei Tong, Brian J. Golbourn, Jonathan R. Krieger, Paul Taylor, Ming Li, Jessica Weiss, Sebastiao N. Martins-Filho, Vibha Raghavan, Yasin Mamatjan, Aafaque A. Khan, Michael Cabanero, Shingo Sakashita, Kugeng Huo, Sameer Agnihotri, Kota Ishizawa, Thomas K. Waddell, Gelareh Zadeh, Kazuhiro Yasufuku, Geoffrey Liu, Frances A. Shepherd, Michael F. Moran () and Ming-Sound Tsao ()
Additional contact information
Shideh Mirhadi: Program in Cell Biology, Hospital for Sick Children
Shirley Tam: University Health Network
Quan Li: University Health Network
Nadeem Moghal: University Health Network
Nhu-An Pham: University Health Network
Jiefei Tong: Program in Cell Biology, Hospital for Sick Children
Brian J. Golbourn: University of Pittsburgh School of Medicine
Jonathan R. Krieger: SPARC BioCentre, Hospital for Sick Children
Paul Taylor: Program in Cell Biology, Hospital for Sick Children
Ming Li: University Health Network
Jessica Weiss: Department of Biostatistics, Princess Margaret Cancer Centre
Sebastiao N. Martins-Filho: University Health Network
Vibha Raghavan: University Health Network
Yasin Mamatjan: University Health Network
Aafaque A. Khan: Program in Cell Biology, Hospital for Sick Children
Michael Cabanero: University Health Network
Shingo Sakashita: University Health Network
Kugeng Huo: University Health Network
Sameer Agnihotri: University of Pittsburgh School of Medicine
Kota Ishizawa: University Health Network
Thomas K. Waddell: University Health Network
Gelareh Zadeh: University Health Network
Kazuhiro Yasufuku: University Health Network
Geoffrey Liu: University Health Network
Frances A. Shepherd: University Health Network
Michael F. Moran: Program in Cell Biology, Hospital for Sick Children
Ming-Sound Tsao: University Health Network

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. Only a fraction of NSCLC harbor actionable driver mutations and there is an urgent need for patient-derived model systems that will enable the development of new targeted therapies. NSCLC and other cancers display profound proteome remodeling compared to normal tissue that is not predicted by DNA or RNA analyses. Here, we generate 137 NSCLC patient-derived xenografts (PDXs) that recapitulate the histology and molecular features of primary NSCLC. Proteome analysis of the PDX models reveals 3 adenocarcinoma and 2 squamous cell carcinoma proteotypes that are associated with different patient outcomes, protein-phosphotyrosine profiles, signatures of activated pathways and candidate targets, and in adenocarcinoma, stromal immune features. These findings portend proteome-based NSCLC classification and treatment and support the PDX resource as a viable model for the development of new targeted therapies.

Date: 2022
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DOI: 10.1038/s41467-022-29444-9

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