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 Wagle; Rong Fan; Franziska Michor; Sandra S. McAllister; Kornelia Polyak

doi:10.1038/s41556-019-0346-x

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

Yonsei Advanced Science Institute

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

27 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 language	English
Pages (from-to)	879-888
Number of pages	10
Journal	Nature Cell Biology
Volume	21
Issue number	7
DOIs	https://doi.org/10.1038/s41556-019-0346-x
Publication status	Published - 2019 Jul 1

Bibliographical note

Funding Information:
We thank the members of the Polyak and Michor laboratories for their critical reading of this manuscript and useful discussions. We thank L. Cameron from the DFCI Confocal Microscopy and Z. Herbert from the DFCI Molecular Biology Core Facility for their dedication and technical expertise. We also thank the staff of the DFCI Animal Facility for their help with the imaging studies. This work was supported by the Dana–Farber Cancer Institute Physical Sciences–Oncology Center (grant no. U54CA143798 to F.M. and K.P.) and Center for Cancer Evolution (F.M. and K.P.), CDRMP Breast Cancer Research Program (grant nos W81XWH-09-1-0561 (A.M.) and W81XWH-14-1-0191 (S.S.M)), Swiss National Science Foundation project no. P2EZP2 175139 (S.C.), NIH (grant nos K99/R00 CA201606-01A1 (M.J.) and R35CA197623 (K.P.)), the Ludwig Center at Harvard (F.M. and K.P.), Novartis Oncology (K.P.), and the Breast Cancer Research Foundation (K.P.).

All Science Journal Classification (ASJC) codes

Cell Biology

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Janiszewska, M., Tabassum, D. P., Castaño, Z., Cristea, S., Yamamoto, K. N., Kingston, N. L., Murphy, K. C., Shu, S., Harper, N. W., Del Alcazar, C. G., Alečković, M., Ekram, M. B., Cohen, O., Kwak, M., Qin, Y., Laszewski, T., Luoma, A., Marusyk, A., Wucherpfennig, K. W., ... Polyak, K. (2019). Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments. Nature Cell Biology, 21(7), 879-888. https://doi.org/10.1038/s41556-019-0346-x

Janiszewska, Michalina ; Tabassum, Doris P. ; Castaño, Zafira ; Cristea, Simona ; Yamamoto, Kimiyo N. ; Kingston, Natalie L. ; Murphy, Katherine C. ; Shu, Shaokun ; Harper, Nicholas W. ; Del Alcazar, Carlos Gil ; Alečković, Maša ; Ekram, Muhammad B. ; Cohen, Ofir ; Kwak, Minsuk ; Qin, Yuanbo ; Laszewski, Tyler ; Luoma, Adrienne ; Marusyk, Andriy ; Wucherpfennig, Kai W. ; Wagle, Nikhil ; Fan, Rong ; Michor, Franziska ; McAllister, Sandra S. ; Polyak, Kornelia. / Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments. In: Nature Cell Biology. 2019 ; Vol. 21, No. 7. pp. 879-888.

@article{a3dcc15d71794c369695f026fd3b734a,

title = "Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments",

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.",

author = "Michalina Janiszewska and Tabassum, {Doris P.} and Zafira Casta{\~n}o and Simona Cristea and Yamamoto, {Kimiyo N.} and Kingston, {Natalie L.} and Murphy, {Katherine C.} and Shaokun Shu and Harper, {Nicholas W.} and {Del Alcazar}, {Carlos Gil} and Ma{\v s}a Ale{\v c}kovi{\'c} and Ekram, {Muhammad B.} and Ofir Cohen and Minsuk Kwak and Yuanbo Qin and Tyler Laszewski and Adrienne Luoma and Andriy Marusyk and Wucherpfennig, {Kai W.} and Nikhil Wagle and Rong Fan and Franziska Michor and McAllister, {Sandra S.} and Kornelia Polyak",

note = "Funding Information: We thank the members of the Polyak and Michor laboratories for their critical reading of this manuscript and useful discussions. We thank L. Cameron from the DFCI Confocal Microscopy and Z. Herbert from the DFCI Molecular Biology Core Facility for their dedication and technical expertise. We also thank the staff of the DFCI Animal Facility for their help with the imaging studies. This work was supported by the Dana–Farber Cancer Institute Physical Sciences–Oncology Center (grant no. U54CA143798 to F.M. and K.P.) and Center for Cancer Evolution (F.M. and K.P.), CDRMP Breast Cancer Research Program (grant nos W81XWH-09-1-0561 (A.M.) and W81XWH-14-1-0191 (S.S.M)), Swiss National Science Foundation project no. P2EZP2 175139 (S.C.), NIH (grant nos K99/R00 CA201606-01A1 (M.J.) and R35CA197623 (K.P.)), the Ludwig Center at Harvard (F.M. and K.P.), Novartis Oncology (K.P.), and the Breast Cancer Research Foundation (K.P.).",

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Janiszewska, M, Tabassum, DP, Castaño, Z, Cristea, S, Yamamoto, KN, Kingston, NL, Murphy, KC, Shu, S, Harper, NW, Del Alcazar, CG, Alečković, M, Ekram, MB, Cohen, O, Kwak, M, Qin, Y, Laszewski, T, Luoma, A, Marusyk, A, Wucherpfennig, KW, Wagle, N, Fan, R, Michor, F, McAllister, SS & Polyak, K 2019, 'Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments', Nature Cell Biology, vol. 21, no. 7, pp. 879-888. https://doi.org/10.1038/s41556-019-0346-x

Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments. / Janiszewska, Michalina; Tabassum, Doris P.; Castaño, Zafira; Cristea, Simona; Yamamoto, Kimiyo N.; Kingston, Natalie L.; Murphy, Katherine C.; Shu, Shaokun; Harper, Nicholas W.; Del Alcazar, Carlos Gil; Alečković, Maša; Ekram, Muhammad B.; Cohen, Ofir; Kwak, Minsuk; Qin, Yuanbo; Laszewski, Tyler; Luoma, Adrienne; Marusyk, Andriy; Wucherpfennig, Kai W.; Wagle, Nikhil; Fan, Rong; Michor, Franziska; McAllister, Sandra S.; Polyak, Kornelia.

In: Nature Cell Biology, Vol. 21, No. 7, 01.07.2019, p. 879-888.

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

TY - JOUR

T1 - Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments

AU - Janiszewska, Michalina

AU - Tabassum, Doris P.

AU - Castaño, Zafira

AU - Cristea, Simona

AU - Yamamoto, Kimiyo N.

AU - Kingston, Natalie L.

AU - Murphy, Katherine C.

AU - Shu, Shaokun

AU - Harper, Nicholas W.

AU - Del Alcazar, Carlos Gil

AU - Alečković, Maša

AU - Ekram, Muhammad B.

AU - Cohen, Ofir

AU - Kwak, Minsuk

AU - Qin, Yuanbo

AU - Laszewski, Tyler

AU - Luoma, Adrienne

AU - Marusyk, Andriy

AU - Wucherpfennig, Kai W.

AU - Wagle, Nikhil

AU - Fan, Rong

AU - Michor, Franziska

AU - McAllister, Sandra S.

AU - Polyak, Kornelia

N1 - Funding Information: We thank the members of the Polyak and Michor laboratories for their critical reading of this manuscript and useful discussions. We thank L. Cameron from the DFCI Confocal Microscopy and Z. Herbert from the DFCI Molecular Biology Core Facility for their dedication and technical expertise. We also thank the staff of the DFCI Animal Facility for their help with the imaging studies. This work was supported by the Dana–Farber Cancer Institute Physical Sciences–Oncology Center (grant no. U54CA143798 to F.M. and K.P.) and Center for Cancer Evolution (F.M. and K.P.), CDRMP Breast Cancer Research Program (grant nos W81XWH-09-1-0561 (A.M.) and W81XWH-14-1-0191 (S.S.M)), Swiss National Science Foundation project no. P2EZP2 175139 (S.C.), NIH (grant nos K99/R00 CA201606-01A1 (M.J.) and R35CA197623 (K.P.)), the Ludwig Center at Harvard (F.M. and K.P.), Novartis Oncology (K.P.), and the Breast Cancer Research Foundation (K.P.).

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

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