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; Ming-Sound Tsao

doi:10.1038/s41467-022-29444-9

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

Nat Commun. 2022 Apr 5;13(1):1811. doi: 10.1038/s41467-022-29444-9.

Authors

Shideh Mirhadi^{1

2}, Shirley Tam³, Quan Li³, Nadeem Moghal³, Nhu-An Pham³, Jiefei Tong¹, Brian J Golbourn⁴, Jonathan R Krieger⁵, Paul Taylor¹, Ming Li³, Jessica Weiss⁶, Sebastiao N Martins-Filho^{3

7}, Vibha Raghavan³, Yasin Mamatjan³, Aafaque A Khan¹, Michael Cabanero^{3

7}, Shingo Sakashita³, Kugeng Huo³, Sameer Agnihotri⁴, Kota Ishizawa⁸, Thomas K Waddell^{8

9}, Gelareh Zadeh^{3

9}, Kazuhiro Yasufuku^{8

9}, Geoffrey Liu^{3

10

11}, Frances A Shepherd^{3

10}, Michael F Moran^{12

13

14}, Ming-Sound Tsao^{15

16

17}

Affiliations

¹ Program in Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
² Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
³ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁴ John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, and Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁵ SPARC BioCentre, Hospital for Sick Children, Toronto, ON, Canada.
⁶ Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, ON, Canada.
⁷ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁸ Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
⁹ Department of Surgery, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, ON, Canada.
¹¹ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹² Program in Cell Biology, Hospital for Sick Children, Toronto, ON, Canada. [email protected].
¹³ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. [email protected].
¹⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. [email protected].
¹⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. [email protected].
¹⁶ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. [email protected].
¹⁷ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Non-Small-Cell Lung* / pathology
Heterografts
Humans
Lung Neoplasms* / genetics
Lung Neoplasms* / pathology
Mice
Mice, SCID
Xenograft Model Antitumor Assays

Grants and funding

FDN-148395/CIHR/Canada