LAUSR

Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in the Unites States with a 5-year survival rate of only 11%. Early diagnosis is very difficult and thus 53% of patients are diagnosed after metastasis has already occurred, with the liver being the most frequently affected site. Both primary tumors and metastases have highly fibrotic stroma. Thus, stromal targeting agents have the potential to benefit patients, even those with metastatic disease. However, in addition to different resident fibroblasts, a study based on a rapid autopsy program of metastatic PDAC patients showed that tumor ECM density is actually lower at sites of liver metastasis compared to the primary tumor. These results highlight some of the differences between the microenvironment of the liver metastatic niche (LMN) compared to that of the primary tumor. Thus, to best help patients, models which recapitulate the LMN are needed. We developed a 3D biomimetic model to co-culture PDAC organoids and host matching primary CAFs to recapitulate the desmoplastic environment of primary PDAC. Our preliminary results show that primary site derived CAFs induce organoid growth, chemoresistance, and ECM remodeling when co-cultured with PDAC organoids. Utilizing paired organoids which metastasized to the liver (LM organoids), we tested if primary site derived CAFs would have the same effect on LMs. Interestingly, we observed that while LM organoids were intrinsically more drug resistant, co-culture with primary site derived CAFs had no effect on chemoresistance or ECM remodeling. Next, we utilized a metastasis associated fibroblast (MAF) liver cell line to investigate the role of MAFs in tumor growth, chemoresistance, and ECM remodeling. Our results show that primary and metastatic organoids use different mechanism to induce ECM stiffness triggered by fibroblast activation and remodeling in their resident fibroblasts. Citation Format: Mahsa Pahlavanneshan, Weikun Xiao, Chae Young Eun, Chang-Il Hwang, Reginald Hill. Developing a 3D biomimetic liver metastatic niche model for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3513.