Camargo Sandra, Moskowitz Ori, Giladi Amir, Levinson Maiia, Balaban Roi, Gola Shani, Raizman Alice, Lipczyc Kelly, Richter Alon, Keren-Khadmy Noa, Barboy Oren, Dugach Yael, Carmi Yaron, Sonnenblick Amir, Cohen Merav
Department of Clinical Microbiology and Immunology, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands.
Nat Cancer. 2025 Mar;6(3):540-558. doi: 10.1038/s43018-025-00924-3. Epub 2025 Mar 7.
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.
乳腺组织重塑和细胞可塑性由多谱系通讯激活；然而，促进乳腺癌的动态信号传导仍不清楚。在这里，通过对乳腺发育和癌变过程中的单细胞和物理相互作用细胞（PIC）进行RNA测序，我们发现中性粒细胞在早期发育过程中短暂出现，并在晚期癌中与肿瘤细胞的物理相互作用中再次出现。中性粒细胞异质性分析确定了与年龄和癌症阶段相关的转录状态。将配体-受体和PIC测序分析与各种功能实验相结合，揭示了一个物理和分泌的促肿瘤信号微环境。这种方法表明，中性粒细胞被肿瘤激活的巨噬细胞招募，并与肿瘤细胞发生物理相互作用，增加肿瘤细胞的增殖和侵袭特性，以及内皮细胞增殖和血管生成。在中性粒细胞-PIC中上调的分子程序与晚期乳腺癌患者较低的生存率相关。我们基于相互作用的观点突出了乳腺癌治疗的潜在分子靶点和生物标志物。
