Poster - #UCLA-46 - Keywords: Pancreatic Cancer Fibroblasts Liver Metastasis ECM stiffness

Investigating the Effect of ECM Stiffness in a 3D Biomimetic Liver Metastatic Niche Model for Pancreatic Cancer

Mahsa Pahlavan1,2, Weikun Xiao2, Chae Young Eun2, Chang-Il Hwang3, and Reginald Hill2
1Department of Biomedical Engineering, University of Southern California, Los Angeles, USA 2Lawrence J. Ellison Institute for Transformative Medicine of USC, University of Southern California, Los Angeles, USA 3Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California Davis, Davis, USA

ABSTRACT:
Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in US 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 liver being the most frequently affected site. Both primary tumors and metastases have highly fibrotic stroma, causing extracellular matrix (ECM) remodeling which leads to increased stiffness. Thus, models designed to recapitulate the stiff liver metastatic niche (LMN) are needed to develop therapies to eradicate metastatic lesions. To address this problem, we aim to design a biomimetic model that specifically recapitulates the LMN using a collagen rich ECM that mimics the metastatic site using LMN-derived fibroblasts, paired primary PDAC organoids, and matching LMN organoids derived from a mouse model of PDAC. CAFs make up a large portion of the tumor bulk in PDAC and are known to travel to the metastatic site. That is why we first investigated the role of primary site derived CAFs in LMN development. Our results showed that primary tumor-derived organoid lines showed increased chemoresistance when co-cultured with primary CAFs. However, no difference in chemoresistance was observed in LMN organoids when primary CAFs were present. Moreover, while primary CAFs caused ECM remodeling in primary site-derived organoid co-cultures, ECM remodeling was not observed in the LMN organoids co-cultured with primary site-derived CAFs. We hypothesize there are cell intrinsic differences between the primary site and metastatic site derived tumor cells that make the metastatic tumor cells less dependent on the external influence from primary site derived CAFs. Next, we will perform studies with LMN-derived fibroblasts and compare the results with the data we have obtained with primary-site derived CFAs in order to elucidate how fibroblast source, and any resulting changes in ECM remodeling, may contribute to LMN organoid growth and chemoresistance.