原发瘤微团脱落是肿瘤早期播散首要环节，成团侵袭是其前奏。侵袭前缘细胞与微环境相互作用获得不完全EMT(partial EMT,pEMT)是启动微团脱离的关键，机制不清。肿瘤相关巨噬细胞的TAM是肿瘤微环境中主要的间质细胞，可协助癌细胞超早期转移。早期乳腺癌浸润的TAM多分布在侵袭边缘，提示TAM与前缘细胞功能有关。本课题前期①CD44特异高表达于管腔型乳腺癌成团侵袭的前缘细胞表面，与pEMT及侵袭有关②TAM可诱导前缘细胞由CD44s向CD44v转变，CD44模式动态转变与可塑性有关。提示侵袭前缘TAM-CD44s/v可能与前缘细胞侵袭脱落有关。本课题拟首次探讨TAM调节CD44模式转变（s↔v）对前缘细胞成团侵袭/脱落的调控及机制。内容①阐明乳腺癌TAM-CD44s/v在前缘细胞获得pEMT侵袭表型及微团脱落中作用②探讨TAM对其CD44s/CD44v的调控机制，力从新视角阐明转移机制。

The micro-mass shedding of primary tumor as cell clusters is the first step in the early spread of breast cancers, and the collective cell invasion is the prelude. The partial epithelial-mesenchymal transition (pEMT) state of the leader cells, acquired during collective invasion, was a key factor for initiation of the micro-mass shedding. However, it is unknown what drives their enhanced metastatic potential and what are the vulnerabilities in the leader cells. Tumor-associated macrophages (TAM) are the most abundant stromal cells in the tumor microenvironment, which can orchestrate super-early metastasis of cancer cells before the manifestation of breast tumors. TAM is mostly distributed at the leading invasion edge around early-stage breast cancers, and only a small amount is located at the inner of tumor mass. These reports suggested that TAMs might have effect on the invasive behavior of the leader cells. Previous work from our laboratory showed that: (1) CD44 was specifically highly expressed on the surface of the leader cells of collective invasion in luminal-like breast cancers, which was related to pEMT and invasion; (2) TAM can induce the switching of CD44s to CD44v in the leader cells. The alternative splicing of CD44 expression pattern leads to an induction of cell plasticity. It suggested that TAM/CD44s/v switching in the leading edge of tumor invasion might be related to the invasion and shedding of the leader cells. For the first time, this project try to understand the effects of TAM on the CD44 splice isoform switching of the leader cells during collective invasion and micro-mass shedding, including two parts: (1) To study the role of CD44 switching induced by TAMs in triggering the formation of pEMT phenotype and micro-mass shedding of the leader cells. (2) To explore the regulation mechanism of TAM on CD44s/CD44v switching. The project may provide a new insight to elucidate the mechanism of metastasis in breast cancer.