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

Eric S. Martin, Peter J. Belmont, Mark J. Sinnamon, Larissa Georgeon Richard, Jing Yuan, Erin M. Coffee, Jatin Roper, Lydia Lee, Pedram Heidari, Sophia Y. Lunt, Gautam Goel, Xiadong Ji, Zhi Xie, Tao Xie, John Lamb, Scott L. Weinrich, Todd VanArsdale, Roderick T. Bronson, Ramnik J. Xavier, Matthew G. Vander Heiden & 3 others Julie L C Kan, Umar Mahmood, Kenneth E. Hung

Research output: Research - peer-reviewArticle

  • 18 Citations

Abstract

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 fromGEMM 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.

LanguageEnglish (US)
Pages2929-2940
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number11
DOIs
StatePublished - Jun 1 2013
Externally publishedYes

Profile

Drug Discovery
Colonic Neoplasms
Colorectal Neoplasms
Transplants
Cell Line
Neoplasms
In Vitro Techniques
Therapeutics
1-Phosphatidylinositol 4-Kinase
Neoplasm Genes
Glycolysis
Microarray Analysis
Mitogen-Activated Protein Kinases
Tumor Cell Line
Transcriptome
Research Design
Transplantation
Glucose
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. Clinical Cancer Research, 19(11), 2929-2940. DOI: 10.1158/1078-0432.CCR-12-2307

Development of a colon cancer GEMM-derived orthotopic transplant model for drug discovery and validation. / Martin, Eric S.; Belmont, Peter J.; Sinnamon, Mark J.; Richard, Larissa Georgeon; Yuan, Jing; Coffee, Erin M.; Roper, Jatin; Lee, Lydia; Heidari, Pedram; Lunt, Sophia Y.; Goel, Gautam; Ji, Xiadong; Xie, Zhi; Xie, Tao; Lamb, John; Weinrich, Scott L.; VanArsdale, Todd; Bronson, Roderick T.; Xavier, Ramnik J.; Vander Heiden, Matthew G.; Kan, Julie L C; Mahmood, Umar; Hung, Kenneth E.

In: Clinical Cancer Research, Vol. 19, No. 11, 01.06.2013, p. 2929-2940.

Research output: Research - peer-reviewArticle

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 2013, 'Development of a colon cancer GEMM-derived orthotopic transplant model for drug discovery and validation' Clinical Cancer Research, vol 19, no. 11, pp. 2929-2940. DOI: 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. Clinical Cancer Research. 2013 Jun 1;19(11):2929-2940. Available from, DOI: 10.1158/1078-0432.CCR-12-2307
Martin, Eric S. ; Belmont, Peter J. ; Sinnamon, Mark J. ; Richard, Larissa Georgeon ; Yuan, Jing ; Coffee, Erin M. ; Roper, Jatin ; Lee, Lydia ; Heidari, Pedram ; Lunt, Sophia Y. ; Goel, Gautam ; Ji, Xiadong ; Xie, Zhi ; Xie, Tao ; Lamb, John ; Weinrich, Scott L. ; VanArsdale, Todd ; Bronson, Roderick T. ; Xavier, Ramnik J. ; Vander Heiden, Matthew G. ; Kan, Julie L C ; Mahmood, Umar ; Hung, Kenneth E./ Development of a colon cancer GEMM-derived orthotopic transplant model for drug discovery and validation. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 11. pp. 2929-2940
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abstract = "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 fromGEMM 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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T1 - Development of a colon cancer GEMM-derived orthotopic transplant model for drug discovery and validation

AU - Martin,Eric S.

AU - Belmont,Peter J.

AU - Sinnamon,Mark J.

AU - Richard,Larissa Georgeon

AU - Yuan,Jing

AU - Coffee,Erin M.

AU - Roper,Jatin

AU - Lee,Lydia

AU - Heidari,Pedram

AU - Lunt,Sophia Y.

AU - Goel,Gautam

AU - Ji,Xiadong

AU - Xie,Zhi

AU - Xie,Tao

AU - Lamb,John

AU - Weinrich,Scott L.

AU - VanArsdale,Todd

AU - Bronson,Roderick T.

AU - Xavier,Ramnik J.

AU - Vander Heiden,Matthew G.

AU - Kan,Julie L C

AU - Mahmood,Umar

AU - Hung,Kenneth E.

PY - 2013/6/1

Y1 - 2013/6/1

N2 - 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 fromGEMM 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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