Integrated spatial proteomic analysis of breast cancer heterogeneity unravels cancer cell phenotypic plasticity

Mariya Mardamshina, Shiri Karagach, Vishnu Mohan, Gali Arad, Daniela Necula, Ofra Golani, Liat Fellus-Alyagor, Anjana Shenoy, Kateryna Krol, Daniel Pirak, Nitay Itzhacky, Irina Marin, Bruria Shalmon, Yoseph Addadi, Roded Sharan, Einav Gal-Yam, Iris Barshack and Tamar Geiger ()
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Mariya Mardamshina: Tel Aviv University, School of Medicine
Shiri Karagach: Weizmann Institute of Science, Department of Molecular Cell Biology
Vishnu Mohan: Weizmann Institute of Science, Department of Molecular Cell Biology
Gali Arad: Tel Aviv University, School of Medicine
Daniela Necula: Tel Hashomer, Pathology Institute, Sheba Medical Center
Ofra Golani: Weizmann Institute of Science, Department of Life Sciences Core Facilities
Liat Fellus-Alyagor: Weizmann Institute of Science, Department of Veterinary Resources
Anjana Shenoy: Tel Aviv University, School of Medicine
Kateryna Krol: Tel Hashomer, Pathology Institute, Sheba Medical Center
Daniel Pirak: Tel Aviv University, School of Computer Science
Nitay Itzhacky: Tel Aviv University, School of Computer Science
Irina Marin: Tel Hashomer, Pathology Institute, Sheba Medical Center
Bruria Shalmon: Tel Hashomer, Pathology Institute, Sheba Medical Center
Yoseph Addadi: Weizmann Institute of Science, Department of Life Sciences Core Facilities
Roded Sharan: Tel Aviv University, School of Computer Science
Einav Gal-Yam: Tel Hashomer, Oncology Department, Sheba Medical Center
Iris Barshack: Tel Hashomer, Pathology Institute, Sheba Medical Center
Tamar Geiger: Weizmann Institute of Science, Department of Molecular Cell Biology

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Tumor heterogeneity drives drug resistance and relapse, influencing immune evasion and tumor progression. While intratumor heterogeneity has been extensively studied at the genomic level, its functional outcomes and interactions with the tumor microenvironment remain underexplored. In contrast, the functional outcome of heterogeneity and the interplay with the tumor microenvironment have not been addressed. In this study, we integrate multi-region spatial MS-based proteomics of 280 tumor regions, exome sequencing, and imaging to investigate spatial proteomic heterogeneity in breast cancer. Our findings reveal increased proteomic heterogeneity with tumor progression, independent of genomic heterogeneity but closely associated with microenvironmental differences. Integration with immune and stromal imaging highlighted a dynamic interplay where low-grade tumors exhibit constrained immune infiltration, and upon progression to higher grades, macrophages and T cells infiltrate. However, anti-inflammatory pathways involving kynurenine and prostaglandins are more highly expressed in infiltrated regions, suggesting that anti-tumorigenic activities are inhibited. Integration with the global protein network provides potential targetable mediators of immune evasion in breast cancer that can serve as the basis for future development of personalized breast cancer therapies.

Date: 2025
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DOI: 10.1038/s41467-025-65477-6

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