Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization.
| العنوان: | Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization. |
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| المؤلفون: | Ben-Chetrit N; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA.; These authors contributed equally., Niu X; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA.; These authors contributed equally.; Present address: Genentech, Inc., South San Francisco, CA, USA., Sotelo J; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA., Swett AD; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA., Rajasekhar VK; Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Jiao MS; Center of Comparative Medicine and Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Stewart CM; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA., Bhardwaj P; Department of Medicine, Weill Cornell Medical College, New York, NY, USA., Kottapalli S; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA., Ganesan S; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA., Loyher PL; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Potenski C; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA., Hannuna A; Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel., Brown KA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA., Iyengar NM; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Giri DD; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Lowe SW; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA., Healey JH; Center of Comparative Medicine and Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Geissmann F; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sagi I; Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel., Joyce JA; Department of Oncology and Ludwig Institute for Cancer Research, University of Lausanne, Switzerland., Landau DA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 27. Date of Electronic Publication: 2023 Oct 27. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Tumor-infiltrating macrophages support critical steps in tumor progression, and their accumulation in the tumor microenvironment (TME) is associated with adverse outcomes and therapeutic resistance across human cancers. In the TME, macrophages adopt diverse phenotypic alterations, giving rise to heterogeneous immune activation states and induction of cell cycle. While the transcriptional profiles of these activation states are well-annotated across human cancers, the underlying signals that regulate macrophage heterogeneity and accumulation remain incompletely understood. Here, we leveraged a novel ex vivo organotypic TME (oTME) model of breast cancer, in vivo murine models, and human samples to map the determinants of functional heterogeneity of TME macrophages. We identified a subset of F4/80 high Sca-1+ self-renewing macrophages maintained by type-I interferon (IFN) signaling and requiring physical contact with cancer-associated fibroblasts. We discovered that the contact-dependent self-renewal of TME macrophages is mediated via Notch4, and its inhibition abrogated tumor growth of breast and ovarian carcinomas in vivo , as well as lung dissemination in a PDX model of triple-negative breast cancer (TNBC). Through spatial multi-omic profiling of protein markers and transcriptomes, we found that the localization of macrophages further dictates functionally distinct but reversible phenotypes, regardless of their ontogeny. Whereas immune-stimulatory macrophages (CD11C+CD86+) populated the tumor epithelial nests, the stroma-associated macrophages (SAMs) were proliferative, immunosuppressive (Sca-1+CD206+PD-L1+), resistant to CSF-1R depletion, and associated with worse patient outcomes. Notably, following cessation of CSF-1R depletion, macrophages rebounded primarily to the SAM phenotype, which was associated with accelerated growth of mammary tumors. Our work reveals the spatial determinants of macrophage heterogeneity in breast cancer and highlights the disruption of macrophage self-renewal as a potential new therapeutic strategy. Competing Interests: The authors. D.A.L and N.B.-C are co-inventors on a patent application filed by Weill Cornell Medicine related to the findings in this manuscript. DAL has served as a consultant for Abbvie, AstraZeneca and Illumina and is on the Scientific Advisory Board of Mission Bio, Pangea, Alethiomics, and C2i Genomics; DAL has received prior research funding from BMS, 10x Genomics, Ultima Genomics, and Illumina unrelated to the current manuscript. |
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| معلومات مُعتمدة: | DP2 CA239065 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: breast cancer; macrophage self-renewal; spatial transcriptomics; tumor microenvironment; tumor-associated macrophages |
| تواريخ الأحداث: | Date Created: 20231114 Latest Revision: 20231130 |
| رمز التحديث: | 20231130 |
| مُعرف محوري في PubMed: | PMC10634790 |
| DOI: | 10.1101/2023.10.24.563749 |
| PMID: | 37961223 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2023.10.24.563749 |
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