Neutrophils Physically Interact with Tumor Cells to Form a Signaling Niche Promoting Breast Cancer Aggressiveness

Overview

Journal Nat Cancer

Specialty Oncology

Date 2025 Mar 7

PMID 40055573

Authors

Sandra Camargo

Ori Moskowitz

Amir Giladi

Maiia Levinson

Roi Balaban

Shani Gola

Alice Raizman

Kelly Lipczyc

Alon Richter

Noa Keren-Khadmy

Oren Barboy

Yael Dugach

Yaron Carmi

Amir Sonnenblick

Merav Cohen

Affiliations

Soon will be listed here.

Abstract

Tissue remodeling and cell plasticity in the mammary gland are activated by multilineage communications; however, the dynamic signaling promoting breast cancer remains unclear. Here, by RNA sequencing of single cells and physically interacting cells (PICs) along mammary gland development and carcinogenesis, we uncovered that neutrophils appear transiently during early development and re-emerge in physical interaction with tumor cells in advanced carcinoma. Neutrophil heterogeneity analysis characterized transcriptional states linked to age and cancer stage. Integrating ligand-receptor and PIC sequencing analyses with various functional experiments unveiled a physical and secreted protumorigenic signaling niche. This approach revealed that neutrophils are recruited by tumor-activated macrophages and physically interact with tumor cells, increasing tumor cell proliferative and invasive properties, as well as endothelial proliferation and angiogenesis. The molecular program upregulated in neutrophil-PICs correlates with lower survival in advanced breast cancer patients. Our interaction-driven perspective highlights potential molecular targets and biomarkers for breast cancer treatment.

References

Pal B, Chen Y, Milevskiy M, Vaillant F, Prokopuk L, Dawson C . Single cell transcriptome atlas of mouse mammary epithelial cells across development. Breast Cancer Res. 2021; 23(1):69. PMC: 8243869. DOI: 10.1186/s13058-021-01445-4. View

Valdes-Mora F, Salomon R, Gloss B, Law A, Venhuizen J, Castillo L . Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype. Cell Rep. 2021; 35(2):108945. DOI: 10.1016/j.celrep.2021.108945. View

Attalla S, Taifour T, Bui T, Muller W . Insights from transgenic mouse models of PyMT-induced breast cancer: recapitulating human breast cancer progression in vivo. Oncogene. 2020; 40(3):475-491. PMC: 7819848. DOI: 10.1038/s41388-020-01560-0. View

Jaillon S, Ponzetta A, Di Mitri D, Santoni A, Bonecchi R, Mantovani A . Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer. 2020; 20(9):485-503. DOI: 10.1038/s41568-020-0281-y. View

Zhu Y, Padgett L, Dinh H, Marcovecchio P, Blatchley A, Wu R . Identification of an Early Unipotent Neutrophil Progenitor with Pro-tumoral Activity in Mouse and Human Bone Marrow. Cell Rep. 2018; 24(9):2329-2341.e8. PMC: 6542273. DOI: 10.1016/j.celrep.2018.07.097. View

Szczerba B, Castro-Giner F, Vetter M, Krol I, Gkountela S, Landin J . Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature. 2019; 566(7745):553-557. DOI: 10.1038/s41586-019-0915-y. View

Gong Z, Li Q, Shi J, Li P, Hua L, Shultz L . Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis. Sci Immunol. 2023; 8(80):eadd5204. PMC: 10067025. DOI: 10.1126/sciimmunol.add5204. View

Adler O, Zait Y, Cohen N, Blazquez R, Doron H, Monteran L . Reciprocal interactions between innate immune cells and astrocytes facilitate neuroinflammation and brain metastasis via lipocalin-2. Nat Cancer. 2023; 4(3):401-418. DOI: 10.1038/s43018-023-00519-w. View

Maas R, Soukup K, Fournier N, Massara M, Galland S, Kornete M . The local microenvironment drives activation of neutrophils in human brain tumors. Cell. 2023; 186(21):4546-4566.e27. DOI: 10.1016/j.cell.2023.08.043. View

10.

Giladi A, Cohen M, Medaglia C, Baran Y, Li B, Zada M . Dissecting cellular crosstalk by sequencing physically interacting cells. Nat Biotechnol. 2020; 38(5):629-637. DOI: 10.1038/s41587-020-0442-2. View

11.

Aleckovic M, Li Z, Zhou N, Qiu X, Lulseged B, Foidart P . Combination Therapies to Improve the Efficacy of Immunotherapy in Triple-negative Breast Cancer. Mol Cancer Ther. 2023; 22(11):1304-1318. PMC: 10618734. DOI: 10.1158/1535-7163.MCT-23-0303. View

12.

Cohen M, Giladi A, Barboy O, Hamon P, Li B, Zada M . The interaction of CD4 helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response. Nat Cancer. 2022; 3(3):303-317. DOI: 10.1038/s43018-022-00338-5. View

13.

Bui T, Yalom L, Ning E, Urbanczyk J, Ren X, Herrnreiter C . Tissue-specific reprogramming leads to angiogenic neutrophil specialization and tumor vascularization in colorectal cancer. J Clin Invest. 2024; 134(7). PMC: 10977994. DOI: 10.1172/JCI174545. View

14.

Dimitrov D, Turei D, Garrido-Rodriguez M, Burmedi P, Nagai J, Boys C . Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data. Nat Commun. 2022; 13(1):3224. PMC: 9184522. DOI: 10.1038/s41467-022-30755-0. View

15.

Zhu M, Che Q, Liao Y, Wang H, Wang J, Chen Z . Oncostatin M activates STAT3 to promote endometrial cancer invasion and angiogenesis. Oncol Rep. 2015; 34(1):129-38. DOI: 10.3892/or.2015.3951. View

16.

Petzold T, Zhang Z, Ballesteros I, Saleh I, Polzin A, Thienel M . Neutrophil "plucking" on megakaryocytes drives platelet production and boosts cardiovascular disease. Immunity. 2022; 55(12):2285-2299.e7. PMC: 9767676. DOI: 10.1016/j.immuni.2022.10.001. View

17.

Atalay P, Ozpolat B . PIM3 Kinase: A Promising Novel Target in Solid Cancers. Cancers (Basel). 2024; 16(3). PMC: 10854964. DOI: 10.3390/cancers16030535. View

18.

Choi H, Kwon J, Cho M, Sun Y, Zheng X, Wang J . Targeting DDX3X Triggers Antitumor Immunity via a dsRNA-Mediated Tumor-Intrinsic Type I Interferon Response. Cancer Res. 2021; 81(13):3607-3620. PMC: 8597981. DOI: 10.1158/0008-5472.CAN-20-3790. View

19.

Quandt E, Masip N, Hernandez-Ortega S, Sanchez-Botet A, Gasa L, Fernandez-Elorduy A . CDK6 is activated by the atypical cyclin I to promote E2F-mediated gene expression and cancer cell proliferation. Mol Oncol. 2023; 17(7):1228-1245. PMC: 10323892. DOI: 10.1002/1878-0261.13438. View

20.

Esteva-Font C, Jin B, Verkman A . Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice. FASEB J. 2013; 28(3):1446-53. PMC: 3929666. DOI: 10.1096/fj.13-245621. View