CD44v5 domain regulates crosstalk between TNBC cells and tumor‐associated macrophages by enhancing the IL‐4R/STAT3 axis

• Published in: Cancer science Vol. 115; no. 7; pp. 2235 - 2253
• Main Authors: Dai, Yanhua, Ji, Zhongjian, Liang, Hongyan, Jiang, Meng, Wang, Lan, Bao, Xinyi, Liu, Jiaren, Liu, Ming, Yang, Chun
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2024; John Wiley and Sons Inc
• Subjects: Angiogenesis; Animals; Antibiotics; Breast cancer; CD44v5 domain; Cell activation; Cell culture; Cell Line, Tumor; Female; Humans; Hyaluronan Receptors - metabolism; IL‐4R; Interleukin 4; Interleukin 6; Interleukin-4 - metabolism; Interleukin-4 Receptor alpha Subunit - genetics; Interleukin-4 Receptor alpha Subunit - metabolism; Interleukin-6 - metabolism; Internalization; Macrophages; Medical prognosis; Medical research; Metastases; Metastasis; Mice; Original; ORIGINAL ARTICLE; Penicillin; Polarization; Polymerase chain reaction; Signal Transduction; Stat3 protein; STAT3 Transcription Factor - metabolism; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; triple‐negative breast cancer; Tumor cells; Tumor Microenvironment; Tumor-Associated Macrophages - immunology; Tumor-Associated Macrophages - metabolism; Tumors; tumor‐associated macrophages; CD44v5 domain; tumor‐associated macrophages; IL‐4R; triple‐negative breast cancer
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.16200

Triple‐negative breast cancer (TNBC) has greater infiltration of M2‐like macrophages (TAMs), which enhances cancer cell invasion and leads to a poor prognosis. TNBC progression is mediated by both tumor cells and the tumor microenvironment (TME). Here we elucidate the mechanism of the interaction between TNBC cells and TAMs. In this study, we confirmed that CD44v5 is highly expressed in TNBC, which drives TNBC cell metastasis and promotes TAM polarization by co‐localizing with IL4Rα and inhibiting its internalization and degradation, thereby promoting activation of the STAT3/IL6 signaling axis. At the same time, TAMs also facilitate TNBC cell metastasis by secreting IL‐4, IL‐6, and other cytokines, in which the IL‐4/IL‐4R/STAT3/IL‐6 signaling axis plays the same role for TNBC cells responding to TAMs. Moreover, we found that the above progress could be suppressed when the CD44v5 domain was blocked. We demonstrated that the CD44v5/IL‐4R/STAT3/IL‐6 signaling pathway plays a key role in TNBC cell metastasis, and in TNBC cells inducing TAM polarization and responding to TAMs, promoting metastasis. Collectively, we suggest that the CD44v5 domain may be a promising target for regulating the TME of TNBC as well as treating TNBC. Triple‐negative breast cancer (TNBC) has been shown to cause greater infiltration and polarization of M2‐like macrophages (TAMs), which enhances cancer cell invasion and leads to a poor prognosis. TNBC progression is mediated by both tumor cells and the tumor microenvironment (TME). Here we elucidate the mechanism of the interaction between TNBC cells and TAMs.