Cancer-associated fibroblast-induced lncRNA UPK1A-AS1 confers platinum resistance in pancreatic cancer via efficient double-strand break repair

Xiang Zhang,Renpeng Xia,Qing Lin,Hongcao Lin,Zhihua Li,Quanbo Zhou,Shangyou Zheng,Rufu Chen,Yuancheng Ye,Rihua He,Chonghui Hu,Guolin Li

doi:10.1038/s41388-022-02253-6

Abstract

The tumor stroma of pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant and heterogeneous population of cancer-associated fibroblasts (CAFs), which are critically involved in chemoresistance. However, the underlying mechanism of CAFs in chemoresistance is unclear. Here, we show that CAFR, a CAF subset derived from platinum-resistant PDAC patients, assumes an iCAF phenotype and produces more IL8 than CAFS isolated from platinum-sensitive PDAC patients. CAFR-derived IL8 promotes oxaliplatin chemoresistance in PDAC. Based on long noncoding RNA (lncRNA) profiling in tumor cells incubated with CAF-CM, we found that UPK1A-AS1, whose expression is directly induced by IL8/NF-kappa B signaling, functions as a chemoresistance-promoting lncRNA and is critical for active IL8-induced oxaliplatin resistance. Impressively, blocking the activation of UPK1A-AS1 expression increases the oxaliplatin sensitivity of tumor cells in vivo. Mechanistically, UPK1A-AS1 strengthens the interaction between Ku70 and Ku80 to facilitate nonhomologous end joining (NHEJ), thereby enhancing DNA double-strand break (DSB) repair. Clinically, UPK1A-AS1 expression is positively correlated with IL8 expression, a poor chemotherapeutic response and a shorter progression-free survival (PFS) time in advanced PDAC patients. Collectively, our study reveals a lncRNA-mediated mechanism of CAF-derived paracrine IL8-dependent oxaliplatin resistance and highlights UPK1A-AS1 as a potential therapeutic target.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal disease despite the application of multiple therapeutic strategies [1]
Cancer-associated fibroblasts (CAFs) were correlated with platinum resistance in PDAC To investigate the inherent heterogeneity of CAFs in chemoresistance, we adopted a clinical model of platinum-based chemotherapy for advanced pancreatic cancer to monitor the diverse response of tumors to drugs
The results showed that the proportion of inflammatory CAFs (iCAFs) was significantly increased in the tissue from the chemoresistant patients before and after chemotherapy (Fig. 1B), while the amounts of myofibroblastic CAFs (myCAFs) and apCAFs did not differ between the chemoresistant and chemosensitive patients (Fig. S1B and D)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal disease despite the application of multiple therapeutic strategies [1]. Cancer-associated fibroblasts (CAFs), a major component of the stroma that undergoes transformation and exhibits heterogeneity during cancer evolution, can perform both tumor-promoting and tumor-suppressive or homeostatic functions in PDAC [5]. One subgroup named inflammatory CAFs (iCAFs) is mainly characterized by the secretion of inflammatory factors (such as IL-6, LIF, IL-1, etc.) and is relatively far from tumor cells, while the other subpopulation, named myofibroblastic CAFs (myCAFs), expresses characteristic proteins, such as a-SMA, TGFβ, and ECM, and is distributed adjacent to tumor cells [9, 11]. Recently, through a single-cell analysis, a subgroup of CAFs (named antigenpresenting CAFs (apCAFs)) that mainly function to mediate the immune response of pancreatic cancer has been found and is mainly characterized by the expression of MHC class II molecules and CD74 [7]. To precisely target the CAF subpopulations that support tumor growth, it is necessary to enhance our understanding of their functions and mechanisms

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Results

Conclusion