Targeting a positive regulatory loop in the tumor-macrophage interaction impairs the progression of clear cell renal cell carcinoma
Targeting a positive regulatory loop in the tumor-macrophage interaction impairs the progression of clear cell renal cell carcinoma
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靶向肿瘤-巨噬细胞相互作用中的正调节环可损害透明细胞肾细胞癌的进展。
DOI：
10.1038/s41418-020-00626-6
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发表时间：
2020-10-02
影响因子：
12.4
通讯作者：
Cui, Xingang
中科院分区：
文献类型：
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作者：
Wang, Chao;Wang, Yuning;Cui, Xingang
虽然肿瘤和肿瘤相关巨噬细胞（TAM）之间的相互作用已被报道促进透明细胞肾细胞癌（ccRCC）的靶向耐药和进展，但相关机制仍不清楚。在此，我们报道了SOX 17在ccRCC中作为一种新的肿瘤抑制因子，并且正调控环SOX 17（低）/雅普/TEAD 1/CCL 5/CCR 5/STAT 3促进ccRCC-TAM相互作用。SOX 17表达普遍下调，与TAM浸润呈负相关，将SOX 17和TAM与现有临床指标TNM分期或SSGN评分相结合，对预测ccRCC患者预后具有更好的准确性。机制上，SOX 17敲低通过促进雅普的转录和核分布激活雅普信号传导，其募集TEAD 1以触发CCL 5转录。然后，CCL 5使巨噬细胞朝向TAM，TAM通过CCL 5/CCR 5和活化STAT 3/SOX 17（低）/雅普促进ccRCC进展。然而，在ccRCC中S 0X 17过表达实现了相反的效果。因此，在ccRCC-TAM相互作用中鉴定了正调控环，SOX 17（低）/雅普/TEAD 1/CCL 5/CCR 5/STAT 3。此外，通过阻断这种正调控网络来靶向肿瘤-TAM相互作用损害了肺转移和原位ccRCC的体内小鼠模型中ccRCC的转移和靶向耐药性。这些发现提供了肿瘤-TAM在ccRCC进展中相互作用的新机制，并为抑制晚期ccRCC中的靶向耐药性和转移提供了潜在靶点。
Although the interaction between tumors and tumor-associated macrophages (TAMs) has been reported to facilitate the targeted drug resistance and progression of clear cell renal cell carcinoma (ccRCC), the related mechanisms remain unknown. Here, we report that SOX17 serves as a novel tumor suppressor in ccRCC and a positive regulatory loop, SOX17(low)/YAP/TEAD1/CCL5/CCR5/STAT3, facilitates the ccRCC-TAM interaction. SOX17 expression was commonly downregulated and negatively correlated with TAM infiltration in ccRCC specimens, and the integration of SOX17 and TAMs with the existing clinical indicators TNM stage or SSIGN score achieved better accuracy for predicting the prognosis of ccRCC patients. Mechanistically, SOX17 knockdown activated YAP signaling by promoting the transcription and nuclear distribution of YAP, which recruited TEAD1 to trigger CCL5 transcription. Then, CCL5 educated macrophages toward TAMs, which reciprocally enhanced ccRCC progression through CCL5/CCR5 and activated STAT3/SOX17(low)/YAP. However, SOX17 overexpression in ccRCC achieved the opposite effect. Thus, a positive regulatory loop, SOX17(low)/YAP/TEAD1/CCL5/CCR5/STAT3, was identified in the ccRCC-TAM interaction. Furthermore, targeting tumor-TAM interactions by blocking this positive regulatory network impaired the metastasis and targeted drug resistance of ccRCC in in vivo mouse models of lung metastasis and orthotopic ccRCC. These findings provide a new mechanism underlying the tumor-TAM interplay in ccRCC progression and present a potential target for inhibiting targeted drug resistance and metastasis in advanced ccRCC.