Abstract A49: LIF-mediated crosstalk between pancreatic stellate and cancer cells and its translational application

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most malignant cancer type with 5-year survival rate less than 8%, largely due to inefficient diagnosis and tenacious drug resistance. The development of dense stroma is its prominent feature, accounting for its aggressive biology and pivotal for its progression and drug resistance. The stroma not only just acts as a mechanical barrier to impede drug access, but also provides a unique growth-permissive environment to promote tumor progression and metastasis and to circumvent immune surveillance. The pancreatic stellate cell (PSC) is a key player in the formation and turnover of pancreatic tumor stroma, and the reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumor progression and metastasis but also sustains their own activation, facilitating a vicious circle to exacerbate tumorigenesis and drug resistance. Moreover, PSC activation occurs very early during PDAC tumorigenesis, and activated PSCs comprise a significant fraction of the tumor mass, providing a rich source of readily detectable factors. Therefore, a better understanding of the communication between PSCs and PCCs should shed light on the vulnerability amenable for PDAC therapy and diagnosis. To comprehensively investigate the process, we performed systematic proteomic analysis of the dynamic changes in both the composition and intracellular signal transduction stimulation of the secretomes of pancreatic stellate cells (PSCs) and pancreatic cancer cells (PCCs). Among many intriguing findings, we revealed leukemia inhibitory factor (LIF) as a key paracrine factor, mainly secreted by activated stromal PSCs, to mediate the intercellular communication. Both pharmacologic LIF blockade and genetic Lifr deletion significantly slow tumor progression and augment chemotherapy efficacy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and EMT status. Moreover, we found that, consistently in both mouse models and human PDAC, aberrant production of LIF in the pancreas is unique to pathologic conditions and correlates with PDAC pathogenesis, and changes in circulating LIF level correlate well with tumor response to therapy. As such, this study established LIF as an attractive therapeutic target and biomarker. Recently, we expanded our analysis by proteomic profiling on human pancreatic normal vs. tumor tissues focused mainly on the secreted and cell-membrane proteins by specific pre-enrichment to catalog the active ligand-receptor pairs and corresponding communications underlying to further broaden our understanding of paracrine interactions between PSCs and PCCs and to explore its potential translational application. Citation Format: Yu Shi, Ruijun Tian, Tony Hunter. LIF-mediated crosstalk between pancreatic stellate and cancer cells and its translational application [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A49.