Tumor-Associated Macrophages Promote Metastasis of Oral Squamous Cell Carcinoma via CCL13 Regulated by Stress Granule

Simple Summary Oral cancer is a devastating disease for humans. Tumor-associated macrophages (TAMs) are notorious tumor promoters. The major TAMs populations in most solid tumors are cancer-promoting M2 TAMs, which play a vital role in mediating the immunosuppressive tumor microenvironment, promoting tumor blood vessel formation and leading to tumor metastasis through the production of tumor-promoting inflammatory factors or chemokines. CCL13 is a crucial pro-tumor chemokine from M2 TAMs. G3BP1 has been reported to trigger tumor metastasis via mediating the cellular stress responses. Hitherto, it is unclear that how M2 TAMs released the CCL13 to promote OSCC metastasis. In the current study, we identified that G3BP1 can facilitate adaptive reactions of macrophages in response to adverse conditions in the tumor microenvironment, and these effects of G3BP1 simultaneously stimulated the expression of CCL13 from M2 TAMs, consequently improving oral cancer metastasis. M2 tumor-associated macrophages (TAMs) have been a well-established promoter of oral squamous cell carcinoma (OSCC) progression. However, the mechanisms of M2 TAMs promoting OSCC metastasis have not been elucidated clearly. This study illustrated the regulatory mechanisms in which M2 TAMs enhance OSCC malignancy in a novel point of view. In this study, mass spectrometry was utilized to analyze the proteins expression profile of M2 type monocyte-derived macrophages (MDMs-M2), whose results revealed the high expression of G3BP1 in M2 macrophages. RNA sequencing analyzed the genome-wide changes upon G3BP1 knockdown in MDMs-M2 and identified that CCL13 was the most significantly downregulated inflammatory cytokines in MDMs-M2. Co-immunoprecipitation and qualitative mass spectrometry were used to identify the proteins that directly interacted with endogenous G3BP1 in MDMs-M2. Elevated stress granule (SG) formation in stressed M2 TAMs enhanced the expression of CCL13, which promoted OSCC metastasis both in vitro and in vivo. For mechanisms, we demonstrated SG formation improved DDX3Y/hnRNPF-mediated CCL13 mRNA stability, thus enhancing CCL13 expression and promoting OSCC metastasis. Collectively, our findings demonstrated for the first time the roles of CCL13 in improving OSCC metastasis and illustrated the molecular mechanisms of CCL13 expression regulated by SG, indicating that the SG-CCL13 axis can be the potential targets for TAM-navigated tumor therapy.