Abstract 1580: Investigating the tumor microenvironment of pancreatic ductal adenocarcinoma with BRCA2 mutation

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancers with a survival rate of less than 12% at 5 years. It is estimated that around 14% of human PDAC contain mutations in genes involved in DNA Damage Repair (DDR), including BRCA1/2, ATM, and others. Additionally, PDAC has an extensive network of extracellular matrix components surrounding the tumor in the stroma, such as cancer-associated fibroblasts, which promote cancer cell growth. The interactions of the tumor with its tumor microenvironment and stroma can bring vulnerabilities that could be targeted if identified. New therapeutic strategies to those targets can be developed for specifically PDAC with DDR mutations. Using publicly available RNA-seq dataset of PDAC patients from The Cancer Genome Atlas (TCGA), I computationally estimated the infiltration of immune and stromal cell types into the tumor. From the analyses, I found that there was a significant difference in the migration of Common Lymphoid Progenitor (CLP) cells into PDAC with mutations to DDR genes. CLP cells usually divide into T-cells, B-cells, and NK cells, suggesting that DDR mutations could cause a more immunogenic environment. There was also a decrease in the infiltration of stromal elements, mainly fibroblasts, into PDAC with mutations to DDR genes. In the experiment I am currently working on, I hypothesize there are also in vivo differences in the infiltration rates of certain immune cell types and fibroblasts into BRCA2-mutated PDAC, since BRCA2 is the most commonly mutated DDR gene in PDAC. For my current experimental design, the mice in the experimental group will be orthotopically implanted with PDAC with Brca2 knockout. The control group will have mice orthotopically implanted with PDAC without Brca2 knockout. After letting the tumors grow for 3 weeks, the mice will be sacrificed and the pancreatic tumors will be collected and stained through trichrome staining. Trichrome staining probes for the stromal cancer-associated fibroblasts. Furthermore, immunohistochemistry (IHC) staining will be done to look for specific populations of cells, such as specific types of fibroblasts, effective and immunosuppressive immune cells including T-cells, B-cells, and NK cells. The aim is to see whether the computational findings in regards to the tumor microenvironment are also reflected in vivo. I will have the data from this experiment by the time of the conference in April 2024. Overall, my project is about investigating the tumor microenvironment and fibroblast abundance in PDAC with BRCA2 knockout mice, using computational data, IHC staining and trichrome staining. Citation Format: Fatimah Al-Musawi, Chang-il Hwang. Investigating the tumor microenvironment of pancreatic ductal adenocarcinoma with BRCA2 mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1580.