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Development of a colon cancer GEMM-derived orthotopic transplant model for drug discovery and validation.

Publication ,  Journal Article
Martin, ES; Belmont, PJ; Sinnamon, MJ; Richard, LG; Yuan, J; Coffee, EM; Roper, J; Lee, L; Heidari, P; Lunt, SY; Goel, G; Ji, X; Xie, Z ...
Published in: Clin Cancer Res
June 1, 2013

PURPOSE: Effective therapies for KRAS-mutant colorectal cancer (CRC) are a critical unmet clinical need. Previously, we described genetically engineered mouse models (GEMM) for sporadic Kras-mutant and non-mutant CRC suitable for preclinical evaluation of experimental therapeutics. To accelerate drug discovery and validation, we sought to derive low-passage cell lines from GEMM Kras-mutant and wild-type tumors for in vitro screening and transplantation into the native colonic environment of immunocompetent mice for in vivo validation. EXPERIMENTAL DESIGN: Cell lines were derived from Kras-mutant and non-mutant GEMM tumors under defined media conditions. Growth kinetics, phosphoproteomes, transcriptomes, drug sensitivity, and metabolism were examined. Cell lines were implanted in mice and monitored for in vivo tumor analysis. RESULTS: Kras-mutant cell lines displayed increased proliferation, mitogen-activated protein kinase signaling, and phosphoinositide-3 kinase signaling. Microarray analysis identified significant overlap with human CRC-related gene signatures, including KRAS-mutant and metastatic CRC. Further analyses revealed enrichment for numerous disease-relevant biologic pathways, including glucose metabolism. Functional assessment in vitro and in vivo validated this finding and highlighted the dependence of Kras-mutant CRC on oncogenic signaling and on aerobic glycolysis. CONCLUSIONS: We have successfully characterized a novel GEMM-derived orthotopic transplant model of human KRAS-mutant CRC. This approach combines in vitro screening capability using low-passage cell lines that recapitulate human CRC and potential for rapid in vivo validation using cell line-derived tumors that develop in the colonic microenvironment of immunocompetent animals. Taken together, this platform is a clear advancement in preclinical CRC models for comprehensive drug discovery and validation efforts.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

June 1, 2013

Volume

19

Issue

11

Start / End Page

2929 / 2940

Location

United States

Related Subject Headings

  • ras Proteins
  • Xenograft Model Antitumor Assays
  • Wnt Signaling Pathway
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Phosphatidylinositol 3-Kinases
  • Oncology & Carcinogenesis
  • Mutation
  • Mitogen-Activated Protein Kinases
  • Mice, Transgenic
 

Citation

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ICMJE
MLA
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Martin, E. S., Belmont, P. J., Sinnamon, M. J., Richard, L. G., Yuan, J., Coffee, E. M., … Hung, K. E. (2013). Development of a colon cancer GEMM-derived orthotopic transplant model for drug discovery and validation. Clin Cancer Res, 19(11), 2929–2940. https://doi.org/10.1158/1078-0432.CCR-12-2307
Martin, Eric S., Peter J. Belmont, Mark J. Sinnamon, Larissa Georgeon Richard, Jing Yuan, Erin M. Coffee, Jatin Roper, et al. “Development of a colon cancer GEMM-derived orthotopic transplant model for drug discovery and validation.Clin Cancer Res 19, no. 11 (June 1, 2013): 2929–40. https://doi.org/10.1158/1078-0432.CCR-12-2307.
Martin ES, Belmont PJ, Sinnamon MJ, Richard LG, Yuan J, Coffee EM, et al. Development of a colon cancer GEMM-derived orthotopic transplant model for drug discovery and validation. Clin Cancer Res. 2013 Jun 1;19(11):2929–40.
Martin, Eric S., et al. “Development of a colon cancer GEMM-derived orthotopic transplant model for drug discovery and validation.Clin Cancer Res, vol. 19, no. 11, June 2013, pp. 2929–40. Pubmed, doi:10.1158/1078-0432.CCR-12-2307.
Martin ES, Belmont PJ, Sinnamon MJ, Richard LG, Yuan J, Coffee EM, Roper J, Lee L, Heidari P, Lunt SY, Goel G, Ji X, Xie Z, Xie T, Lamb J, Weinrich SL, VanArsdale T, Bronson RT, Xavier RJ, Vander Heiden MG, Kan JLC, Mahmood U, Hung KE. Development of a colon cancer GEMM-derived orthotopic transplant model for drug discovery and validation. Clin Cancer Res. 2013 Jun 1;19(11):2929–2940.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

June 1, 2013

Volume

19

Issue

11

Start / End Page

2929 / 2940

Location

United States

Related Subject Headings

  • ras Proteins
  • Xenograft Model Antitumor Assays
  • Wnt Signaling Pathway
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Phosphatidylinositol 3-Kinases
  • Oncology & Carcinogenesis
  • Mutation
  • Mitogen-Activated Protein Kinases
  • Mice, Transgenic