Cancerassociated Fibroblast Derived Cxcl14 Drives Cisplatin Chemoresistance By Enhancing Nucleotide Excision Repair In Bladder Cancer Tinghao Li Kunyao Zhu Hang Tong Yan Sun Junlong Zhu Zijia Qin Junrui Chen Linfeng Wu Xiaoyu Zhang Aimin Wang Xin Gou Hubin Yin Weiyang He by Tinghao Li & Kunyao Zhu & Hang Tong & Yan Sun & Junlong Zhu & Zijia Qin & Junrui Chen & Linfeng Wu & Xiaoyu Zhang & Aimin Wang & Xin Gou & Hubin Yin & Weiyang He instant download after payment.

AbstractBackground A signifcant challenge in bladder cancer treatment is primary chemoresistance, in which cancerassociated fbroblasts (CAFs) in the tumor microenvironment (TME) play a pivotal role. While the contributions of CAFs to tumor progression and drug resistance are well established, the precise molecular mechanisms by which they induce chemoresistance remain unclear. A comprehensive understanding of the efect of TME modulation—particularly through CAFs—on the chemotherapeutic response is crucial for developing efective strategies to overcome chemoresistance and improve patient survival.Methods Primary fbroblasts were isolated from paired clinical samples of bladder cancer tissues and adjacent normal tissues to identify key CAF-derived secretory factors. Bioinformatics analysis, semiquantitative RT‒qPCR, and dualluciferase reporter assays were subsequently used to investigate the functional role and mechanistic basis of CXCL14 in chemoresistance. The therapeutic relevance of these fndings was further evaluated through in vitro and in vivo models, including ex vivo patient-derived organoid (PDO) models, by assessing cisplatin sensitivity and validating therapeutic targeting of the CXCL14-CCR7-STAT3 axis with small molecule inhibitors.Results Compared to normal fbroblasts and CAFs from nonchemoresistance groups, CAFs derived from cisplatinresistant patients demonstrated signifcantly greater paracrine-mediated induction of chemoresistance. Mechanistically, CAF-secreted CXCL14 engaged CCR7 on bladder cancer cells, triggering STAT3 phosphorylation and consequently upregulating the DNA repair gene ERCC4 to promote cisplatin resistance. In vivo validation confrmed that pharmacological CCR7 or STAT3 inhibition markedly reversed chemoresistance and potentiated cisplatin-induced tumor cell death. Notably, STAT3 activation mediated the overexpression of the glycolytic enzymes HK2 and LDHA, resultin