Abstract A062: SFRP2 Silencing Restrains Pancreatic Cancer Growth and Enhances Survival Through Remodeling of the Tumor Microenvironment
TL;DR
Findings identify SFRP2 as a key regulator of PDAC progression and support the development of SFRP2-targeted therapies as a novel treatment strategy for pancreatic cancer.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options. Secreted frizzled-related protein 2 (SFRP2) has emerged as an important mediator of tumor progression by promoting tumor cell survival, immune exhaustion, and angiogenesis. In human PDAC, elevated SFRP2 expression is associated with worse clinical outcomes and is regulated by KRAS. We hypothesized that SFRP2 plays a critical role in PDAC progression and represents a therapeutic target. SFRP2 knockout (KO) and scrambled control cell lines were generated from a KPC-derived murine PDAC cell line using CRISPR/Cas9 gene editing. Successful gene silencing was confirmed by Western blot. Scrambled control and SFRP2 KO cells were orthotopically implanted into the pancreas of C57BL/6J mice. Tumors were harvested 17 days after implantation, weighed, fixed in formalin, and embedded in paraffin (FFPE). Apoptosis was assessed using the TUNEL assay. Multiplex immunofluorescence (IF) identified tumor-associated macrophages (TAM). M1 macrophages were identified using F4/80, CD80, CD86, and iNOS, while M2 macrophages were identified using F4/80, CD206, and CD163. Images were analyzed using inForm software and validated with Phenochart. Targeted proteomic imaging was performed to evaluate extracellular matrix (ECM) proteins. In a separate study, mice bearing scrambled control or SFRP2 KO tumors were monitored for survival and analyzed using Kaplan-Meier methodology. Western blot confirmed successful SFRP2 silencing, with KO cells demonstrating a 75% reduction in SFRP2 protein expression compared with scrambled controls. In vivo, SFRP2 KO tumors were significantly smaller than controls, with mean tumor weights reduced from 1.79 ± 0.15 g to 0.40 ± 0.06 g in SFRP2 KO (n = 6, p < 0.01). TUNEL analysis demonstrated a 3.5-fold increase in apoptosis in SFRP2 KO tumors (26.44 ± 2.23 apoptotic cells per 20× field) compared with controls (8.00 ± 1.80; n = 3, p < 0.0001). Multiplex IF revealed significantly fewer M2 macrophages in SFRP2 KO tumors, with counts decreasing from 71 ± 13 cells in controls to 12 ± 9 cells in KO tumors (n = 4, p < 0.02); with no change in M1 TAM cell counts. The ECM proteome demonstrated significant remodeling following SFRP2 deletion. SFRP2 KO tumors exhibited a 2.3-fold increase in collagen type I alpha 2 (Col1a2) expression (p < 0.005), accompanied by a twofold decrease in collagen type I alpha 1 (Col1a1) expression (p < 0.005). Loss of SFRP2 also significantly improved survival, with mice bearing scrambled control tumors surviving 14 ± 0 days versus 25.08 ± 0.82 days for the SFRP2 KO group (n = 11, p < 0.001). Genetic deletion of tumor-derived SFRP2 increases apoptosis, suppresses tumor growth, remodels the ECM, reduces immunosuppressive M2 macrophage infiltration, and prolongs survival in an orthotopic PDAC mouse model. These findings identify SFRP2 as a key regulator of PDAC progression and support the development of SFRP2-targeted therapies as a novel treatment strategy for pancreatic cancer. Olivia Sweatt, Lillian Hsu, Lety Reyes Angeles, David Wang, Rachel Burge, Rupak Mukherjee, Jack Hyland, Eleanor Hilliard, Shikhar Mehrotra, Michael Ostrowski, Denis Guttridge, Peggi Angel, Nathaniel Dolloff, Nancy Klauber-DeMore. SFRP2 Silencing Restrains Pancreatic Cancer Growth and Enhances Survival Through Remodeling of the Tumor Microenvironment [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A062.
