Cancer stem cells promote lymph nodes metastasis of breast cancer by reprogramming tumor microenvironment

Lin Li; Jianyu Liu; Wenzheng Wang; Yingqiang Fu; Yuhan Deng; Xin Li; Zhuolin Liu; Yuheng Pang; Yangyang Xu; Meisi Yan; Zhigao Li

doi:10.1016/j.tranon.2023.101733

Cancer stem cells promote lymph nodes metastasis of breast cancer by reprogramming tumor microenvironment

Transl Oncol. 2023 Sep:35:101733. doi: 10.1016/j.tranon.2023.101733. Epub 2023 Jul 6.

Authors

Lin Li¹, Jianyu Liu¹, Wenzheng Wang¹, Yingqiang Fu¹, Yuhan Deng¹, Xin Li¹, Zhuolin Liu¹, Yuheng Pang¹, Yangyang Xu¹, Meisi Yan², Zhigao Li³

Affiliations

¹ Harbin Medical University Cancer Hospital, Harbin Medical University, No.150 Haping Rd, Nangang District, Harbin 150081, China.
² Department of Pathology, Harbin Medical University, Harbin, China.
³ Harbin Medical University Cancer Hospital, Harbin Medical University, No.150 Haping Rd, Nangang District, Harbin 150081, China. Electronic address: drzhigaoli@hrbmu.edu.cn.

Abstract

Breast cancer progression and metastasis are governed by a complex interplay within the tumor immune microenvironment (TIME), involving numerous cell types. Lymph node metastasis (LNM) is a key prognostic marker associated with distant organ metastasis and reduced patient survival, but the mechanisms underlying its promotion by breast cancer stem cells (CSCs) remain unclear. Our study sought to unravel how CSCs reprogram TIME to facilitate LNM. Utilizing single-cell RNA sequencing, we profiled TIME in primary cancer and corresponding metastatic lymph node samples from patients at our institution. To verify the derived data, we cultured CSCs and performed validation assays employing flow cytometry and CyTOF. Our analysis revealed distinct differences in cellular infiltration patterns between tumor and LNM samples. Importantly, RAC2 and PTTG1 double-positive CSCs, which exhibit the highest stem-like attributes, were markedly enriched in metastatic lymph nodes. These CSCs are hypothesized to foster metastasis via activation of specific metastasis-related transcription factors and signaling pathways. Additionally, our data suggest that CSCs might modulate adaptive and innate immune cell evolution, thereby further contributing to metastasis. In summary, this study illuminates a critical role of CSCs in modifying TIME to facilitate LNM. The enrichment of highly stem-like CSCs in metastatic lymph nodes offers novel therapeutic targeting opportunities and deepens our understanding of breast cancer metastasis.

Keywords: Breast cancer 1; Cancer stem cells (CSCs) 2; Lymph node metastasis 5; Single-cell RNA sequencing (scRNA-seq) 4; Tumor immune microenvironment (TIME) 3.