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The site of breast cancer metastases dictates their clonal composition and reversible transcriptomic profile

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posted on 03.08.2021, 01:11 by Jean BertheletJean Berthelet, VC Wimmer, HJ Whitfield, Antonin SerranoAntonin Serrano, T Boudier, S Mangiola, Michal Stanislaw Merdas, Farrah El-SaafinFarrah El-Saafin, David Baloyan, Jordan Wilcox, S Wilcox, Adam ParslowAdam Parslow, AT Papenfuss, Belinda YeoBelinda Yeo, Matthias ErnstMatthias Ernst, Bhupinder PalBhupinder Pal, Robin AndersonRobin Anderson, Martine DavisMartine Davis, KL Rogers, F Hollande, Delphine MerinoDelphine Merino
Intratumoral heterogeneity is a driver of breast cancer progression, but the nature of the clonal interactive network involved in this process remains unclear. Here, we optimized the use of optical barcoding to visualize and characterize 31 cancer subclones in vivo. By mapping the clonal composition of thousands of metastases in two clinically relevant sites, the lungs and liver, we found that metastases were highly polyclonal in lungs but not in the liver. Furthermore, the transcriptome of the subclones varied according to their metastatic niche. We also identified a reversible niche-driven signature that was conserved in lung and liver metastases collected during patient autopsies. Among this signature, we found that the tumor necrosis factor–α pathway was up-regulated in lung compared to liver metastases, and inhibition of this pathway affected metastasis diversity. These results highlight that the cellular and molecular heterogeneity observed in metastases is largely dictated by the tumor microenvironment.

Funding

D.M., F.H., and B.P. are supported by the NBCF (Investigator Initiated Research Grant IIRS-19-082). D.M. is supported by Susan G. Komen and Cancer Australia (CCR19606878). F.H. is supported by the National Health and Medical Research Council of Australia (grant no. 1164081) and by a Senior Research Grant from the Tour de Cure Foundation. D.M., M.J.D., and B.Y. are supported by the Grant-in-Aid Scheme administered by Cancer Council Victoria. D.M., B.Y., and R.L.A. are supported by the Love Your Sister Foundation. R.L.A. and M.J.D. also acknowledge fellowship support from NBCF. The contents of the published material are solely the responsibility of the individual authors and do not reflect the views of Cancer Australia or other funding agencies.

History

Publication Date

01/07/2021

Journal

Science Advances

Volume

7

Issue

28

Article Number

ARTN eabf4408

Pagination

17p. (p. 1-17)

Publisher

American Association for the Advancement of Science

ISSN

2375-2548

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

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