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; Joan S. Brugge

doi:10.1038/s41467-020-19584-1

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 NavinGordon B. Mills, Rodrick T. Bronson, Joan S. Brugge

Pharmacology

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

23 Scopus citations

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.

Original language	English (US)
Article number	5799
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19584-1
State	Published - Dec 2020

Bibliographical note

Funding Information:
We thank the Brugge lab members for helpful discussions, Grace Gao for lab management, Dr. Angie Martinez Gakidis for scientific editing and critical review of the paper, Dr. Yiling Lu and the RPPA team at MD Anderson for running the RPPA samples, Dr. Bakhos A. Tannous for the kind gift of the secreted Gaussia Luciferase construct, Dr. Laura Pontano Vaites from Dr. Wade J. Harperʼs lab for providing the amphiregulin lentiviral vector, Dr. Hyo-eun C. Bhang and Dr. Frank Stegmeier for providing the barcode constructs, Min Hu from Dr. Nicholas Navin’s lab for assisting with the CNA analysis, Dr. Myron Peto from Dr. Paul Spellman’s lab for uploading the WES data to NCBI, Anita L. Hawkins and Shumei Wang for their help with the ERBB2 FISH analysis. The time lapse movies were acquired with the support of The Nikon Imaging Center at Harvard Medical School. Whole-slide scans of tissue were acquired at the Neurobiology Imaging Facility at Harvard Medical School. The assay for Luciferase activity was performed at ICCB-Longwood Screening Facility at Harvard Medical School. Financial support: This research was supported by NCI grant CA181543 (Joan S. Brugge) and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Joan S. Brugge and Gordon B Mills), MD Anderson CCSG grant R50 CA221675 (Gordon B. Mills), R33CA214310 and OC130649 (Tan A. Ince), The Knight Cancer Institute (Paul Spell-man), NINDS P30 Core Center Grant #NS072030 (Neurobiology Imaging Core), 5T32GM07133 (Timothy Butler) and 129098-RSG-16-092-01-TBG (Nicholas Navin).

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Naffar-Abu Amara, S., Kuiken, H. J., Selfors, L. M., Butler, T., Leung, M. L., Leung, C. T., Kuhn, E. P., Kolarova, T., Hage, C., Ganesh, K., Panayiotou, R., Foster, R., Rueda, B. R., Aktipis, A., Spellman, P., Ince, T. A., Xiu, J., Oberley, M., Gatalica, Z., ... Brugge, J. S. (2020). Transient commensal clonal interactions can drive tumor metastasis. Nature communications, 11(1), Article 5799. https://doi.org/10.1038/s41467-020-19584-1

Naffar-Abu Amara, S, Kuiken, HJ, Selfors, LM, Butler, T, Leung, ML, Leung, CT, Kuhn, EP, Kolarova, T, Hage, C, Ganesh, K, Panayiotou, R, Foster, R, Rueda, BR, Aktipis, A, Spellman, P, Ince, TA, Xiu, J, Oberley, M, Gatalica, Z, Navin, N, Mills, GB, Bronson, RT & Brugge, JS 2020, 'Transient commensal clonal interactions can drive tumor metastasis', Nature communications, vol. 11, no. 1, 5799. https://doi.org/10.1038/s41467-020-19584-1

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title = "Transient commensal clonal interactions can drive tumor metastasis",

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.",

author = "{Naffar-Abu Amara}, Suha and Kuiken, {Hendrik J.} and Selfors, {Laura M.} and Timothy Butler and Leung, {Marco L.} and Leung, {Cheuk T.} and Kuhn, {Elaine P.} and Teodora Kolarova and Carina Hage and Kripa Ganesh and Richard Panayiotou and Rosemary Foster and Rueda, {Bo R.} and Athena Aktipis and Paul Spellman and Ince, {Tan A.} and Joanne Xiu and Matthew Oberley and Zoran Gatalica and Nicholas Navin and Mills, {Gordon B.} and Bronson, {Rodrick T.} and Brugge, {Joan S.}",

note = "Funding Information: We thank the Brugge lab members for helpful discussions, Grace Gao for lab management, Dr. Angie Martinez Gakidis for scientific editing and critical review of the paper, Dr. Yiling Lu and the RPPA team at MD Anderson for running the RPPA samples, Dr. Bakhos A. Tannous for the kind gift of the secreted Gaussia Luciferase construct, Dr. Laura Pontano Vaites from Dr. Wade J. Harperʼs lab for providing the amphiregulin lentiviral vector, Dr. Hyo-eun C. Bhang and Dr. Frank Stegmeier for providing the barcode constructs, Min Hu from Dr. Nicholas Navin{\textquoteright}s lab for assisting with the CNA analysis, Dr. Myron Peto from Dr. Paul Spellman{\textquoteright}s lab for uploading the WES data to NCBI, Anita L. Hawkins and Shumei Wang for their help with the ERBB2 FISH analysis. The time lapse movies were acquired with the support of The Nikon Imaging Center at Harvard Medical School. Whole-slide scans of tissue were acquired at the Neurobiology Imaging Facility at Harvard Medical School. The assay for Luciferase activity was performed at ICCB-Longwood Screening Facility at Harvard Medical School. Financial support: This research was supported by NCI grant CA181543 (Joan S. Brugge) and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Joan S. Brugge and Gordon B Mills), MD Anderson CCSG grant R50 CA221675 (Gordon B. Mills), R33CA214310 and OC130649 (Tan A. Ince), The Knight Cancer Institute (Paul Spell-man), NINDS P30 Core Center Grant #NS072030 (Neurobiology Imaging Core), 5T32GM07133 (Timothy Butler) and 129098-RSG-16-092-01-TBG (Nicholas Navin). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

doi = "10.1038/s41467-020-19584-1",

language = "English (US)",

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T1 - Transient commensal clonal interactions can drive tumor metastasis

AU - Naffar-Abu Amara, Suha

AU - Kuiken, Hendrik J.

AU - Selfors, Laura M.

AU - Butler, Timothy

AU - Leung, Marco L.

AU - Leung, Cheuk T.

AU - Kuhn, Elaine P.

AU - Kolarova, Teodora

AU - Hage, Carina

AU - Ganesh, Kripa

AU - Panayiotou, Richard

AU - Foster, Rosemary

AU - Rueda, Bo R.

AU - Aktipis, Athena

AU - Spellman, Paul

AU - Ince, Tan A.

AU - Xiu, Joanne

AU - Oberley, Matthew

AU - Gatalica, Zoran

AU - Navin, Nicholas

AU - Mills, Gordon B.

AU - Bronson, Rodrick T.

AU - Brugge, Joan S.

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PY - 2020/12

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N2 - 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.

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Transient commensal clonal interactions can drive tumor metastasis

Abstract

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