外泌体（exosomes）介导的细胞间信息传递对于胰腺癌细胞吉西他滨耐药的作用研究

Tumor heterogeneity is responsible for intrinsic and acquired resistance to therapy in pancreatic cancer. However, the exact mechanisms underlying Cytotoxic resistance of pancreatic cancer remain unclear. Exosomes are secreted by most cells, including tumor cells, and exosomes secreted at one location can alter the behavior of distant cells. Our previous results showed that Exosomes of chemoresistant PANC-1 cells were internalized by and increased GEM resistance of chemosensitive PC cells. Mass spectrometry analysis found that EphA2 was specially enriched in exosomes transferring chemoresistance. The aim of our study is to explore whether EpHA2 in tumor-derived exosomes can transfer chemoresistance between heterogeneous pancreatic cancer (PC) cell lines and act as functional biomarkers to predict treatment response in PC patients. This study will provide clinical diagnosis and treatment for theory evidence. Taken together, this project will enrich the knowledge of Cytotoxic resistance about pancreatic cancer and provide new strategies and potential therapeutic targets for pancreatic cancer treatment.

肿瘤异质性是胰腺癌患者本身固有的和在治疗过程中逐渐获得耐药性的原因。目前，胰腺癌细胞毒性抵抗的确切机制仍不清楚。Exosomes是由大多数细胞分泌的一种小分子囊泡，exosome在细胞之间的交流可以改变细胞的行为。我们前期的研究结果表明，耐药株PANC-1细胞分泌的exosome可以被敏感细胞系所内源化，接受exosome的敏感细胞系耐药性明显增加。质谱分析发现EphA2蛋白在耐药细胞系所分泌的exosome中明显富集高表达。我们研究的目的是探讨exosome携带的EphA2蛋白是否可以在异质性的胰腺癌细胞中传递耐药性，是否可以作为功能性生物标志物来预测胰腺癌患者的治疗反应。本研究为临床诊治提供理论依据。该项目将加深对胰腺癌细胞耐药机制的认识，为胰腺癌的治疗提供新的思路和潜在的治疗靶点。

肿瘤异质性是胰腺癌患者本身固有的和在治疗过程中逐渐获得耐药性的原因。目前, 胰腺癌细胞毒性抵抗的确切机制仍不清楚。Exosomes是由大多数细胞分泌的一种小分子囊泡,exosome在细胞之间的交流可以改变细胞的行为。我们通过细胞毒性试验，LC MS/MS质谱分析实验，siRNA敲除实验等进行胰腺癌细胞功能研究，通过ELISA实验进行人体血清标本研究。我们研究结果表明,耐药株高侵袭细胞系分泌的exosome可以被敏感细胞系所内源化,接受exosome的敏感细胞系耐药性和侵袭性都明显增加。质谱分析发现EphA2蛋白在耐药高侵袭的细胞系所分泌的exosome中明显富集高表达。结果证实exosome携带的EphA2蛋白可以在异质性的胰腺癌细胞中传递耐药性和侵袭性,exosome携带的EphA2蛋白作为无创生物标志物可以预测胰腺癌患者的治疗反应和胰腺癌的早期辅助诊断。本研究为临床诊治提供理论依据。该项目将加深对胰腺癌细胞耐药机制和侵袭机制的认识,为胰腺癌的治疗和早期诊断提供新的思路。