癌相关成纤维细胞重编程在三阴型乳腺癌放疗抵抗中的分子机制研究

放疗可降低TNBC患者局部复发率并提高生存获益。但仍有一部分患者因放疗抵抗导致治疗失败。本项目研究癌间质微环境中CAFs在放疗及交感神经信号刺激下重编程从而促进TNBC放疗抵抗的分子机制。前期结果显示相比CAFs，放疗及β-肾上腺素能受体(β-AR)信号激活处理的CAFs均具有更强的促TNBC放疗抵抗性。放疗促进CAFs中β2-AR基因ADRB2表达上调及CXCL10表达增加，放疗和β-AR信号激活均可诱导CAFs细胞中细胞质染色质片段(CCFs)累积及胞质DNA感应信号通路明显上调活化。因此，申请人从临床现象出发，原创性地提出放疗联合β-AR信号激活协同诱导CAFs重编程为具有更强的促TNBC放疗抵抗的细胞表型的科学假设，借助于测序及基因工程技术等解析其分子机制，聚焦于CCFs-cGAS-STING-CXCL10信号通路，预期可以初步阐明TNBC放疗抵抗的癌间质微环境调控新机制。

Radiotherapy reduce the recurrence rate and improve the survival benefit in triple-negative breast cancer (TNBC) patients. But, still in some TNBC patients, radiotherapy resistance could lead to treatment failure. Cancer-associated fibroblasts (CAFs), as the most essential cells in stromal microenvironment, play an essential role in malignant behavior of cancer. Our lab found that irradiated CAFs and CAFs activated by β-adrenergic receptor (β-AR) signals could both further promote the invasion and clonal survival of TNBC cells compared to the control CAFs. Radiation lead to an increased expression of β-AR gene ADRB2 in CAFs. Both radiation and β-AR signal activation could induce the accumulation of cytoplasmic chromatin fragments (CCFs) and cytosolic DNA-sensing pathway activation in CAFs. Irradiated CAFs express increased CXCL10 level compared to non-irradiated CAFs. Thus, due to radiation treatment and β-AR signal activation, CAFs can be reprogrammed into a higher malignant phenotype which further promote the radioresistance of TNBC cells. Therefore, based on the clinical phenomenon, we proposed that radiotherapy combined with β-AR signal activation could synergistically induce CAFs reprogramming to participate in the radiotherapy resistance of TNBC, and explore the molecular mechanisms focused on the CCFs-cGAS-STING-CXCL10 signaling via gene sequencing and genetic engineering technology. We expect to clarify the novel mechanisms for cancer microenvironment-mediated regulation of radiotherapy resistance.