Abstract A048: TGFBR2 dysfunction rewires cell cycle, MAPK signaling, and migration in pancreatic cancer
TL;DR
The results suggest that PKT tumor aggressiveness may be attributed to preferential activation of cell cycle-associated programs over EMT-associated migration programs, and support G1/S cell cycle regulation as a potential vulnerability for combination therapy with KRASG12D inhibition or chemotherapy in TGFBR2-mutant or TGFBR2-low PDAC.
Abstract
Genetically engineered mouse models of PDAC exhibit marked differences in survival, indicating that certain genetic alterations regulate disease progression. KC (Ptf1a Cre/+; LSL-Kras G12D/+) mice that possess wildtype transforming growth factor-beta receptor 2 (TGFBR2) have a median survival of 13 months, whereas PKT (Ptf1a Cre/+; LSL-Kras G12D/+; Tgfbr2 fl/fl) mice with pancreas-specific TGFBR2 deletion only survive approximately 8 weeks. This difference in survival suggests that loss of TGFBR2 function increases disease aggressiveness in KRAS-driven PDAC; but the exact mechanism is unknown. TGF-β signaling has been shown to suppress proliferation while promoting epithelial-mesenchymal transition (EMT) in advanced PDAC. We hypothesized that if TGFBR2 dysfunction suppresses canonical SMAD-mediated EMT and migration, then constitutive KRAS-MAPK signaling would maintain cell cycle activation and shift PDAC towards a proliferative state. To understand differences in pathway activation, we compared cell lines derived from KC and PKT genetically engineered mouse models. Bulk RNA-sequencing was performed on two KC and two PKT cell lines in duplicate. Differential expression was calculated using edgeR, and gene set enrichment analysis was performed using fgsea. In validation experiments, we used 6 hr serum-starved KC and PKT cells, which were treated with vehicle or 2.5 ng/mL TGF-β1; and then analyzed for canonical TGF-β signaling by western blotting for alterations in pathway proteins as well as assessing scratch wound migration. Transcriptomic analysis of PKT cells indicated a dysfunctional KRAS-MAPK state compared to KC cells. PKT cells were enriched in the Hallmark KRAS gene set, but demonstrated several up and downregulated effectors in the KEGG MAPK gene set; PKT cells also downregulated the Hallmark EMT gene set. Notably, PKT cells significantly upregulated CCND1 and downregulated CKDN2A and CDKN2B expression. Additionally, TGF-β1 treated PKT cell lines showed minimal increases in p-SMAD2/3 and SNAI1 levels on western blots compared to KC cell lines. Unlike KC cells, TGF-β1 treated PKT cells did not demonstrate a robust migratory response compared to vehicle treatment. TGFBR2 dysfunction in KRASG12D-driven PDAC is associated with an alteration in cell cycle regulators, mixed MAPK pathway activity, and decreased canonical TGF-β signaling. These results suggest that PKT tumor aggressiveness may be attributed to preferential activation of cell cycle-associated programs over EMT-associated migration programs. These findings support G1/S cell cycle regulation as a potential vulnerability for combination therapy with KRASG12D inhibition or chemotherapy in TGFBR2-mutant or TGFBR2-low PDAC. Vincent M. Lam, Richard M. Walsh, Bailey A. Bye, Mariana T. Rückert, Michael N. VanSaun. TGFBR2 dysfunction rewires cell cycle, MAPK signaling, and migration in pancreatic cancer [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 A048.