Spatial and Temporal Mapping of Breast Cancer Lung Metastases Identify TREM2 Macrophages as Regulators of the Metastatic Boundary

Ido Yofe, Tamar Shami, Noam Cohen, Tomer Landsberger, Fadi Sheban, Liat Stoler-Barak, Adam Yalin, Truong San Phan, Baoguo Li, Lea Monteran, Ye’Ela Scharff, Amir Giladi, Miriam Elbaz, Eyal David, Anna Gurevich-Shapiro, Chamutal Gur, Ziv Shulman, Neta Erez, Ido Amit

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Cancer mortality primarily stems from metastatic recurrence, emphasizing the urgent need for developing effective metastasis-targeted immunotherapies. To better understand the cellular and molecular events shaping metastatic niches, we used a spontaneous breast cancer lung metastasis model to create a single-cell atlas spanning different metastatic stages and regions. We found that premetastatic lungs are infiltrated by inflammatory neutrophils and monocytes, followed by the accumulation of suppressive macrophages with the emergence of metastases. Spatial profiling revealed that metastasis-associated immune cells were present in the metastasis core, with the exception of TREM2+ regulatory macrophages uniquely enriched at the metastatic invasive margin, consistent across both murine models and human patient samples. These regulatory macrophages (Mreg) contribute to the formation of an immune-suppressive niche, cloaking tumor cells from immune surveillance. Our study provides a compendium of immune cell dynamics across metastatic stages and niches, informing the development of metastasis-targeting immunotherapies.

Original languageEnglish
Pages (from-to)2610-2631
Number of pages22
JournalCancer Discovery
Volume13
Issue number12
DOIs
StatePublished - 12 Dec 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 American Association for Cancer Research.

Funding

We thank members of the Amit and Erez labs for feedback, Noa David Geller from the Scientific Illustration unit of the Weizmann Institute for artwork, and Katia Pozyuchenko from the Tel Aviv Sourasky Medical Center Institutional BioBank for help obtaining patient samples. This work was supported by a Breakthrough Award from the United States DoD (CDMRP BCRP Award ID W81XWH2110394; I. Amit and N. Erez). I. Amit is an Eden and Steven Romick Professorial Chair, supported by the Howard Hughes Medical Institute (HHMI) International Research Scholar award, funded by the European Union ERC Advanced Grant (no. 101055341-TRO-JAN-Cell), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—NeuroMac Project-ID 259373024—TRR 167, the Israel Science Foundation (ISF) grant no. 1944/22, the Helen and Martin Kimmel Award for Innovative Investigation, the ISF Israel Precision Medicine Program (IPMP) 607/20, the MBZUAI-WIS Joint Program for Artificial Intelligence Research, the Dwek Institute for Cancer Therapy Research, the Moross Integrated Cancer Center, and the Swiss Society Institute for Cancer Prevention Research. N. Erez is supported by the Israel Cancer Research Foundation (ICRF), the Israel Science Foundation Personalized Medicine Program (ISF IPMP #3495/19), the TRANSCAN-3 program, Worldwide Cancer Research, the Emerson Collective, and the Richard Eimert Research Fund on Solid Tumors. Z. Shulman is supported by ISF (1090/18), Research Career Development Award (RCDA) (18-703-R), and Beverley Lubrach Abshez Initiative for Ovarian and Female Reproductive System Cancers (Israel Cancer Research Fund). Z. Shulman is a member of the European Molecular Biology Organization (EMBO) Young Investigator Program. I. Yofe was supported by a Cancer Research Institute Irvington Fellowship from the Cancer Research Institute. The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. We thank members of the Amit and Erez labs for feedback, Noa David Geller from the Scientific Illustration unit of the Weizmann Institute for artwork, and Katia Pozyuchenko from the Tel Aviv Sourasky Medical Center Institutional BioBank for help obtaining patient samples. This work was supported by a Breakthrough Award from the United States DoD (CDMRP BCRP Award ID W81XWH2110394; I. Amit and N. Erez). I. Amit is an Eden and Steven Romick Professorial Chair, supported by the Howard Hughes Medical Institute (HHMI) International Research Scholar award, funded by the European Union ERC Advanced Grant (no. 101055341-TROJAN-Cell), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—NeuroMac Project-ID 259373024—TRR 167, the Israel Science Foundation (ISF) grant no. 1944/22, the Helen and Martin Kimmel Award for Innovative Investigation, the ISF Israel Precision Medicine Program (IPMP) 607/20, the MBZUAI-WIS Joint Program for Artificial Intelligence Research, the Dwek Institute for Cancer Therapy Research, the Moross Integrated Cancer Center, and the Swiss Society Institute for Cancer Prevention Research. N. Erez is supported by the Israel Cancer Research Foundation (ICRF), the Israel Science Foundation Personalized Medicine Program (ISF IPMP #3495/19), the TRANSCAN-3 program, Worldwide Cancer Research, the Emerson Collective, and the Richard Eimert Research Fund on Solid Tumors. Z. Shulman is supported by ISF (1090/18), Research Career Development Award (RCDA) (18-703-R), and Bever-ley Lubrach Abshez Initiative for Ovarian and Female Reproductive System Cancers (Israel Cancer Research Fund). Z. Shulman is a member of the European Molecular Biology Organization (EMBO) Young Investigator Program. I. Yofe was supported by a Cancer Research Institute Irvington Fellowship from the Cancer Research Institute.

FundersFunder number
Bever-ley Lubrach Abshez Initiative for Ovarian and Female Reproductive System Cancers
Beverley Lubrach Abshez Initiative for Ovarian and Female Reproductive System Cancers
Dwek Institute for Cancer Therapy Research
European Union ERC101055341-TROJAN-Cell
Helen and Martin Kimmel award for innovative investigation
IPMP607/20
ISF Israel Precision Medicine Program
Israel Science Foundation Personalized Medicine Program3495/19
MBZUAI-WIS Joint Program for Artificial Intelligence Research
Moross Integrated Cancer Center
Richard Eimert Research Fund on Solid Tumors1090/18, 18-703-R
Swiss Society Institute for Cancer Prevention Research
United States DoDW81XWH2110394
Howard Hughes Medical Institute
Cancer research institute
Israel Cancer Research Fund
European Molecular Biology Organization
Deutsche Forschungsgemeinschaft259373024
Israel Science Foundation1944/22

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