Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/46096
Title: Heterogeneity of Myc expression in breast cancer exposes pharmacological vulnerabilities revealed through executable mechanistic modeling
Authors: Piterman, N
Kreuzaler, P
Clarke, MA
Brown, EJ
Wilson, CH
Kortlever, RM
Littlewood, T
Evans, GI
Fisher, J
First Published: 14-Oct-2019
Publisher: National Academy of Sciences
Citation: Proceedings of the National Academy of Sciences, 2019
Abstract: Cells with higher levels of Myc proliferate more rapidly and supercompetitively eliminate neighboring cells. Nonetheless, tumor cells in aggressive breast cancers typically exhibit significant and stable heterogeneity in their Myc levels, which correlates with refractoriness to therapy and poor prognosis. This suggests that Myc heterogeneity confers some selective advantage on breast tumor growth and progression. To investigate this, we created a traceable MMTV-Wnt1–driven in vivo chimeric mammary tumor model comprising an admixture of low-Myc– and reversibly switchable high-Myc–expressing clones. We show that such tumors exhibit interclonal mutualism wherein cells with high-Myc expression facilitate tumor growth by promoting protumorigenic stroma yet concomitantly suppress Wnt expression, which renders them dependent for survival on paracrine Wnt provided by low-Myc–expressing clones. To identify any therapeutic vulnerabilities arising from such interdependency, we modeled Myc/Ras/p53/Wnt signaling cross talk as an executable network for low-Myc, for high-Myc clones, and for the 2 together. This executable mechanistic model replicated the observed interdependence of high-Myc and low-Myc clones and predicted a pharmacological vulnerability to coinhibition of COX2 and MEK. This was confirmed experimentally. Our study illustrates the power of executable models in elucidating mechanisms driving tumor heterogeneity and offers an innovative strategy for identifying combination therapies tailored to the oligoclonal landscape of heterogenous tumors.
DOI Link: 10.1073/pnas.1903485116
ISSN: 1091-6490
Links: https://www.pnas.org/content/early/2019/10/14/1903485116
http://hdl.handle.net/2381/46096
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2019. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1903485116/-/DCSupplemental.
Appears in Collections:Published Articles, Dept. of Computer Science

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