Transient commensal clonal interactions can drive tumor metastasis

Suha Naffar-Abu Amara, Hendrik J. Kuiken, Laura M. Selfors, Timothy Butler, Marco L. Leung, Cheuk T. Leung, Elaine P. Kuhn, Teodora Kolarova, Carina Hage, Kripa Ganesh, Richard Panayiotou, Rosemary Foster, Bo R. Rueda, Athena Aktipis, Paul Spellman, Tan A. Ince, Joanne Xiu, Matthew Oberley, Zoran Gatalica, Nicholas Navin, Gordon B. Mills, Rodrick T. Bronson and Joan S. Brugge ()
Additional contact information
Suha Naffar-Abu Amara: Harvard Medical School
Hendrik J. Kuiken: Harvard Medical School
Laura M. Selfors: Harvard Medical School
Timothy Butler: Oregon Health & Science University Portland
Marco L. Leung: University of Texas MD Anderson Cancer Center
Cheuk T. Leung: Harvard Medical School
Elaine P. Kuhn: Harvard Medical School
Teodora Kolarova: Harvard Medical School
Carina Hage: Harvard Medical School
Kripa Ganesh: Harvard Medical School
Richard Panayiotou: Harvard Medical School
Rosemary Foster: Vincent Center for Reproductive Biology and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital
Bo R. Rueda: Vincent Center for Reproductive Biology and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital
Athena Aktipis: Arizona State University
Paul Spellman: Oregon Health & Science University Portland
Tan A. Ince: Weill Cornell Medicine
Joanne Xiu: Caris Life Sciences
Matthew Oberley: Caris Life Sciences
Zoran Gatalica: Caris Life Sciences
Nicholas Navin: University of Texas MD Anderson Cancer Center
Gordon B. Mills: Oregon Health and Science University Knight Cancer Institute
Rodrick T. Bronson: Rodent Histopathology Core, Harvard Medical School
Joan S. Brugge: Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract The extent and importance of functional heterogeneity and crosstalk between tumor cells is poorly understood. Here, we describe the generation of clonal populations from a patient-derived ovarian clear cell carcinoma model which forms malignant ascites and solid peritoneal tumors upon intraperitoneal transplantation in mice. The clonal populations are engineered with secreted Gaussia luciferase to monitor tumor growth dynamics and tagged with a unique DNA barcode to track their fate in multiclonal mixtures during tumor progression. Only one clone, CL31, grows robustly, generating exclusively malignant ascites. However, multiclonal mixtures form large solid peritoneal metastases, populated almost entirely by CL31, suggesting that transient cooperative interclonal interactions are sufficient to promote metastasis of CL31. CL31 uniquely harbors ERBB2 amplification, and its acquired metastatic activity in clonal mixtures is dependent on transient exposure to amphiregulin, which is exclusively secreted by non-tumorigenic clones. Amphiregulin enhances CL31 mesothelial clearance, a prerequisite for metastasis. These findings demonstrate that transient, ostensibly innocuous tumor subpopulations can promote metastases via “hit-and-run” commensal interactions.

Date: 2020
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DOI: 10.1038/s41467-020-19584-1

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