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ResearchIn-Press PreviewCell biologyOncology Free access | 10.1172/JCI143557

Hierarchical tumor heterogeneity mediated by cell contact between distinct genetic subclones

Swathi Karthikeyan,1 Ian G. Waters,1 Lauren Dennison,1 David Chu,1 Joshua Donaldson,2 Dong Ho Shin,2 D. Marc Rosen,1 Paula I. Gonzalez-Ericsson,3 Violeta Sanchez,3 Melinda E. Sanders,3 Morgan V. Pantone,4 Riley E. Bergman,4 Brad A. Davidson,4 Sarah C. Reed,4 Daniel J. Zabransky,1 Karen Cravero,1 Kelly Kyker-Snowman,1 Berry Button,1 Hong Yuen Wong,2 Paula J. Hurley,2 Sarah Croessmann,2 and Ben Park4

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Karthikeyan, S. in: JCI | PubMed | Google Scholar

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Waters, I. in: JCI | PubMed | Google Scholar |

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Dennison, L. in: JCI | PubMed | Google Scholar |

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

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1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

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1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

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1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

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1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

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1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

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1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

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1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

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1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Bergman, R. in: JCI | PubMed | Google Scholar |

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

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1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

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1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Zabransky, D. in: JCI | PubMed | Google Scholar |

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Cravero, K. in: JCI | PubMed | Google Scholar

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Kyker-Snowman, K. in: JCI | PubMed | Google Scholar

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Button, B. in: JCI | PubMed | Google Scholar

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Wong, H. in: JCI | PubMed | Google Scholar

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Hurley, P. in: JCI | PubMed | Google Scholar

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

Find articles by Croessmann, S. in: JCI | PubMed | Google Scholar

1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

3Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, United States of America

4Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

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Published February 2, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI143557.
Copyright © 2021, American Society for Clinical Investigation
Published February 2, 2021 - Version history
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Abstract

Intratumor heterogeneity is an important mediator of poor outcomes in many cancers, including breast cancer. Genetic subclones frequently contribute to this heterogeneity, however their growth dynamics and interactions remain poorly understood. PIK3CA and HER2 alterations are known to co-exist in breast and other cancers. Herein, we present data that describe the ability of oncogenic PIK3CA mutant cells to induce the proliferation of quiescent HER2 mutant cells through a cell-contact mediated mechanism. Interestingly, the HER2 cells proliferated to become the major subclone over PIK3CA counterparts both in vitro and in vivo. Furthermore, this phenotype was observed in both hormone receptor positive and negative cell lines, and was dependent on the expression of fibronectin from mutant PIK3CA cells. Analysis of human tumors demonstrated similar HER2:PIK3CA clonal dynamics and fibronectin expression. Our study provides insights into non-random subclonal architecture of heterogenous tumors, which may aid understanding of tumor evolution and future strategies for personalized medicine.

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