Abstract 1724P
Background
Cancer associated fibroblasts (CAFs) play a key role in the tumor microenvironment by promoting ideal circumstances for cancer cell proliferation, angiogenesis, metastasis, and chemo-resistance. Pancreatic ductal adenocarcinoma (PDAC) growth is fueled by autocrine and paracrine interaction between tumors and cancer-associated fibroblasts and macrophages in the tumor microenvironment. We recently discovered that a family of proteins with sequence similarity to 20-member C (FAM20C), a novel secreted kinase that phosphorylates secretory proteins or an ectodomain of membrane proteins containing an S-x-E motif, promotes cancer progression and metastasis through tumor associated macrophages (TAMs), implying a novel role for stromal remodeling in tumors. The purpose of this study was to demonstrate FAM20C's potential for metastasis in the tumor microenvironment by validating CAF development using pancreatic stellate cells (PSC) and mesenchymal stem cells (MSC), which are primary sources of CAF.
Methods
The conditioned medium of FAM20C-overexpressed cells, which reflected the pancreatic cancer milieu, was used to confirm the effect on differentiation of MSCs or PSCs into iCAF, as well as the microenvironment remodeling effect in pancreatic cancer orthotopic mouse model.
Results
Under the conditioned medium of FAM20C-overexpressing CFPAC-1 cells, the mRNA expression of α-smooth muscle actin (α-SMA), a hallmark of myofibroblastic CAFs (myCAFs) was reduced in both MSCs and PSCs. In contrast, iCAF marker expression was dramatically elevated, including fibroblast activation protein (FAP), IL-6, and IL-1. Moreover, FAM20C secretion promoted collagen accumulation and migration. Furthermore, tumor growth was accelerated in an orthotopic model using FAM20C-overexpressing pancreatic cancer cells derived from patients. Collagen was also considerably deposited in the stroma as compared to the control cell-injected orthotopic model.
Conclusions
FAM20C might be a critical regulator of PDAC progression by remodeling microenvironment including TAM, CAF and extracellular matrix in pancreatic cancer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This research was supported by National Cancer Center, Korea (No.2210980).
Disclosure
All authors have declared no conflicts of interest.