Su Liangping, Wu Sangqing, Huang Cheng, Zhuo Xianhua, Chen Jiali, Jiang Xue, Kong Xiangzhan, Lv Cui, Xu Qiuping, Han Ping, Huang Xiaoming, Wong Ping-Pui
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou, 510120, China.
Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
NPJ Precis Oncol. 2023 Oct 11;7(1):102. doi: 10.1038/s41698-023-00460-2.
Conventional chemotherapy targets malignant cells without evaluating counter protection from the tumor microenvironment that often causes treatment failure. Herein, we establish chemoresistant fibroblasts (rCAFs) as regulators of neoadjuvant chemotherapeutic (NACT) response in head and neck squamous cell carcinoma (HNSCC). Clinically, high expression of CAF-related gene signature correlates with worse prognosis and chemotherapeutic response in multiple cancers, while the population of CAFs in the residual tumors of chemoresistant HNSCC patients remains unchanged after NACT treatment, compared to chemosensitive patients. Using a murine cancer model or patient-derived organoid, and primary CAFs isolated from chemo-sensitive (sCAFs) or -resistant patients, we show that rCAFs, but not sCAFs, are resistant to chemotherapy-induced apoptosis while reducing HNSCC cell chemosensitivity via paracrine signals. Combined multi-omics and biochemical analyses indicate an elevated PI3K/AKT/p65 driven cell survival and cytokine production in rCAFs, while rCAF-secreted TGFα promotes cancer cell chemoresistance by activating EGFR/Src/STAT3 survival signaling axis. Treatment with anti-EGFR cetuximab restores the chemosensitivity of tumors derived from co-injection of cancer cells and rCAFs in vivo, while the serum level of TGFα determines NACT response in HNSCC patients. Overall, our findings uncover a novel insight whereby the crosstalk between tumor cell and rCAF determines chemotherapeutic response and prognosis in cancer patients.
传统化疗靶向恶性细胞时未评估肿瘤微环境的反向保护作用,而这种保护作用常常导致治疗失败。在此,我们将化学抗性成纤维细胞(rCAF)确立为头颈部鳞状细胞癌(HNSCC)新辅助化疗(NACT)反应的调节因子。临床上,CAF相关基因特征的高表达与多种癌症的较差预后和化疗反应相关,而与化疗敏感患者相比,化疗耐药的HNSCC患者残余肿瘤中CAF的数量在NACT治疗后保持不变。使用小鼠癌症模型或患者来源的类器官,以及从化疗敏感(sCAF)或耐药患者中分离出的原代CAF,我们发现rCAF而非sCAF对化疗诱导的凋亡具有抗性,同时通过旁分泌信号降低HNSCC细胞的化学敏感性。联合多组学和生化分析表明,rCAF中PI3K/AKT/p65驱动的细胞存活和细胞因子产生增加,而rCAF分泌的TGFα通过激活EGFR/Src/STAT3存活信号轴促进癌细胞的化学抗性。在体内,用抗EGFR西妥昔单抗治疗可恢复由共注射癌细胞和rCAF产生的肿瘤的化学敏感性,而TGFα的血清水平决定了HNSCC患者的NACT反应。总体而言,我们的研究结果揭示了一种新的见解,即肿瘤细胞与rCAF之间的相互作用决定了癌症患者的化疗反应和预后。