Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments

Michalina Janiszewska, Doris P. Tabassum, Zafira Castaño, Simona Cristea, Kimiyo N. Yamamoto, Natalie L. Kingston, Katherine C. Murphy, Shaokun Shu, Nicholas W. Harper, Carlos Gil Del Alcazar, Maša Alečković, Muhammad B. Ekram, Ofir Cohen, Minsuk Kwak, Yuanbo Qin, Tyler Laszewski, Adrienne Luoma, Andriy Marusyk, Kai W. Wucherpfennig, Nikhil WagleRong Fan, Franziska Michor, Sandra S. McAllister, Kornelia Polyak

Research output: Contribution to journalArticlepeer-review

95 Citations (Scopus)

Abstract

Most human tumours are heterogeneous, composed of cellular clones with different properties present at variable frequencies. Highly heterogeneous tumours have poor clinical outcomes, yet the underlying mechanism remains poorly understood. Here, we show that minor subclones of breast cancer cells expressing IL11 and FIGF (VEGFD) cooperate to promote metastatic progression and generate polyclonal metastases composed of driver and neutral subclones. Expression profiling of the epithelial and stromal compartments of monoclonal and polyclonal primary and metastatic lesions revealed that this cooperation is indirect, mediated through the local and systemic microenvironments. We identified neutrophils as a leukocyte population stimulated by the IL11-expressing minor subclone and showed that the depletion of neutrophils prevents metastatic outgrowth. Single-cell RNA-seq of CD45+ cell populations from primary tumours, blood and lungs demonstrated that IL11 acts on bone-marrow-derived mesenchymal stromal cells, which induce pro-tumorigenic and pro-metastatic neutrophils. Our results indicate key roles for non-cell-autonomous drivers and minor subclones in metastasis.

Original languageEnglish
Pages (from-to)879-888
Number of pages10
JournalNature Cell Biology
Volume21
Issue number7
DOIs
Publication statusPublished - 2019 Jul 1

Bibliographical note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.

All Science Journal Classification (ASJC) codes

  • Cell Biology

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