Molecular heterogeneity of non-small cell lung carcinoma patient-derived xenografts closely reflect their primary tumors

Dennis Wang, Nhu An Pham, Jiefei Tong, Shingo Sakashita, Ghassan Allo, Lucia Kim, Naoki Yanagawa, Vibha Raghavan, Yuhong Wei, Christine To, Quang M. Trinh, Maud H.W. Starmans, Michelle A. Chan-Seng-Yue, Dianne Chadwick, Lei Li, Chang Qi Zhu, Ni Liu, Ming Li, Sharon Lee, Vladimir IgnatchenkoDan Strumpf, Paul Taylor, Nadeem Moghal, Geoffrey Liu, Paul C. Boutros, Thomas Kislinger, Melania Pintilie, Igor Jurisica, Frances A. Shepherd, John Douglas Mcpherson, Lakshmi Muthuswamy, Michael F. Moran, Ming Sound Tsao

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Availability of lung cancer models that closely mimic human tumors remains a significant gap in cancer research, as tumor cell lines and mouse models may not recapitulate the spectrum of lung cancer heterogeneity seen in patients. We aimed to establish a patient-derived tumor xenograft (PDX) resource from surgically resected non-small cell lung cancer (NSCLC). Fresh tumor tissue from surgical resection was implanted and grown in the subcutaneous pocket of non-obese severe combined immune deficient (NOD SCID) gamma mice. Subsequent passages were in NOD SCID mice. A subset of matched patient and PDX tumors and non-neoplastic lung tissues were profiled by whole exome sequencing, single nucleotide polymorphism (SNP) and methylation arrays, and phosphotyrosine (pY)-proteome by mass spectrometry. The data were compared to published NSCLC datasets of NSCLC primary and cell lines. 127 stable PDXs were established from 441 lung carcinomas representing all major histological subtypes: 52 adenocarcinomas, 62 squamous cell carcinomas, one adeno-squamous carcinoma, five sarcomatoid carcinomas, five large cell neuroendocrine carcinomas, and two small cell lung cancers. Somatic mutations, gene copy number and expression profiles, and pY-proteome landscape of 36 PDXs showed greater similarity with patient tumors than with established cell lines. Novel somatic mutations on cancer associated genes were identified but only in PDXs, likely due to selective clonal growth in the PDXs that allows detection of these low allelic frequency mutations. The results provide the strongest evidence yet that PDXs established from lung cancers closely mimic the characteristics of patient primary tumors.

Original languageEnglish (US)
Pages (from-to)662-673
Number of pages12
JournalInternational Journal of Cancer
Volume140
Issue number3
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

Keywords

  • copy number aberration
  • DNA methylation
  • mass spectrometry
  • non-small cell lung cancer
  • phosphotyrosine-proteomics
  • transcriptome
  • whole exome next generation sequencing
  • xenograft

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

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    Wang, D., Pham, N. A., Tong, J., Sakashita, S., Allo, G., Kim, L., Yanagawa, N., Raghavan, V., Wei, Y., To, C., Trinh, Q. M., Starmans, M. H. W., Chan-Seng-Yue, M. A., Chadwick, D., Li, L., Zhu, C. Q., Liu, N., Li, M., Lee, S., ... Tsao, M. S. (2017). Molecular heterogeneity of non-small cell lung carcinoma patient-derived xenografts closely reflect their primary tumors. International Journal of Cancer, 140(3), 662-673. https://doi.org/10.1002/ijc.30472