Chimeric mouse tumor models reveal differences in pathway activation between ERBB family-and KRAS-dependent lung adenocarcinomas

Yinghui Zhou; William M. Rideout; Tong Zi; Angela Bressel; Shailaja Reddypalli; Rebecca Rancourt; Jin Kyeung Woo; James W. Horner; Lynda Chin; M. Isabel Chiu; Marcus Bosenberg; Tyler Jacks; Steven C. Clark; Ronald A. Depinho; Murray O. Robinson; Joerg Heyer

doi:10.1038/nbt.1595

Chimeric mouse tumor models reveal differences in pathway activation between ERBB family-and KRAS-dependent lung adenocarcinomas

Yinghui Zhou, William M. Rideout, Tong Zi, Angela Bressel, Shailaja Reddypalli, Rebecca Rancourt, Jin Kyeung Woo, James W. Horner, Lynda Chin, M. Isabel Chiu, Marcus Bosenberg, Tyler Jacks, Steven C. Clark, Ronald A. Depinho, Murray O. Robinson, Joerg Heyer

Genomic Medicine

Research output: Contribution to journal › Article › peer-review

65 Scopus citations

Abstract

To recapitulate the stochastic nature of human cancer development, we have devised a strategy for generating mouse tumor models that involves stepwise genetic manipulation of embryonic stem (ES) cells and chimera generation. Tumors in the chimeric animals develop from engineered cells in the context of normal tissue. Adenocarcinomas arising in an allelic series of lung cancer models containing HER2 (also known as ERBB2), KRAS or EGFR oncogenes exhibit features of advanced malignancies. Treatment of EGFR L858R and KRAS G12V chimeric models with an EGFR inhibitor resulted in near complete tumor regression and no response to the treatment, respectively, accurately reflecting previous clinical observations. Transcriptome and immunohistochemical analyses reveal that PI3K pathway activation is unique to ERBB family tumors whereas KRAS-driven tumors show activation of the JNK/SAP pathway, suggesting points of therapeutic intervention for this difficult-to-treat tumor category.

Original language	English (US)
Pages (from-to)	71-78
Number of pages	8
Journal	Nature biotechnology
Volume	28
Issue number	1
DOIs	https://doi.org/10.1038/nbt.1595
State	Published - Jan 2010

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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Zhou, Y., Rideout, W. M., Zi, T., Bressel, A., Reddypalli, S., Rancourt, R., Woo, J. K., Horner, J. W., Chin, L., Chiu, M. I., Bosenberg, M., Jacks, T., Clark, S. C., Depinho, R. A., Robinson, M. O., & Heyer, J. (2010). Chimeric mouse tumor models reveal differences in pathway activation between ERBB family-and KRAS-dependent lung adenocarcinomas. Nature biotechnology, 28(1), 71-78. https://doi.org/10.1038/nbt.1595

Zhou, Y, Rideout, WM, Zi, T, Bressel, A, Reddypalli, S, Rancourt, R, Woo, JK, Horner, JW, Chin, L, Chiu, MI, Bosenberg, M, Jacks, T, Clark, SC, Depinho, RA, Robinson, MO & Heyer, J 2010, 'Chimeric mouse tumor models reveal differences in pathway activation between ERBB family-and KRAS-dependent lung adenocarcinomas', Nature biotechnology, vol. 28, no. 1, pp. 71-78. https://doi.org/10.1038/nbt.1595

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title = "Chimeric mouse tumor models reveal differences in pathway activation between ERBB family-and KRAS-dependent lung adenocarcinomas",

abstract = "To recapitulate the stochastic nature of human cancer development, we have devised a strategy for generating mouse tumor models that involves stepwise genetic manipulation of embryonic stem (ES) cells and chimera generation. Tumors in the chimeric animals develop from engineered cells in the context of normal tissue. Adenocarcinomas arising in an allelic series of lung cancer models containing HER2 (also known as ERBB2), KRAS or EGFR oncogenes exhibit features of advanced malignancies. Treatment of EGFR L858R and KRAS G12V chimeric models with an EGFR inhibitor resulted in near complete tumor regression and no response to the treatment, respectively, accurately reflecting previous clinical observations. Transcriptome and immunohistochemical analyses reveal that PI3K pathway activation is unique to ERBB family tumors whereas KRAS-driven tumors show activation of the JNK/SAP pathway, suggesting points of therapeutic intervention for this difficult-to-treat tumor category.",

author = "Yinghui Zhou and Rideout, {William M.} and Tong Zi and Angela Bressel and Shailaja Reddypalli and Rebecca Rancourt and Woo, {Jin Kyeung} and Horner, {James W.} and Lynda Chin and Chiu, {M. Isabel} and Marcus Bosenberg and Tyler Jacks and Clark, {Steven C.} and Depinho, {Ronald A.} and Robinson, {Murray O.} and Joerg Heyer",

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AU - Chin, Lynda

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AU - Bosenberg, Marcus

AU - Jacks, Tyler

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AU - Depinho, Ronald A.

AU - Robinson, Murray O.

AU - Heyer, Joerg

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Chimeric mouse tumor models reveal differences in pathway activation between ERBB family-and KRAS-dependent lung adenocarcinomas

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