Abstract A012: Context-dependent role of TGM2 in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, driven by accumulating genetic alterations and sustained by a fibrotic, immunosuppressive tumor microenvironment. We previously identified Transgultaminase 2 (TGM2), a stress-inducible enzyme involved in extracellular matrix remodeling and cell survival, as a critical downstream effector of oncogenic KRAS signaling. In the KrasG12D mouse model (KC), genetic deletion of Tgm2 almost completely protected mice from developing PDAC, establishing TGM2 as a key mediator of tumor initiation. PDAC progression, however, depends on additional genetic alterations in key tumor suppressor genes, such as TP53, SMAD4, and p16INK4A. That said, we next asked whether it could also contribute to PDAC progression. To address this, we initially examined TGM2 expression in representative KrasG12D-based mouse models carrying individual deletions in Trp53 (KPC), Smad4 (KSC), or p16Ink4a (KIC). TGM2 expression was markedly elevated in KPC mice, modestly increased in KIC mice, and unchanged in KSC mice. To functionally assess TGM2’s role in more aggressive disease resembling human PDAC, we made use of the KPC model to evaluate the impact of deleting Tgm2 on disease progression. Interestingly, while Tgm2 deletion in KPC mice led to a modest increase in survival, it did not prevent the development of aggressive PDAC. Histological analysis revealed that tumors from TGM2-deficient KPC mice (TKPC) retained the altered architecture and metastatic behavior characteristic of KPC tumors, indicating that TGM2 is dispensable for PDAC progression once the disease has advanced beyond the initiation stage. Mechanistically, the lack of TGM2 upregulation in KSC mice suggested a potential link between TGF-β signaling and TGM2 expression. Transcriptomic analyses of KC tumors using public datasets revealed that the upregulation in TGM2 expression strongly correlates with increased TGF-β signaling, and in vitro assays confirmed that TGF-β induces TGM2 expression in a Smad4-dependent manner, as shown using both wild-type and SMAD4-deleted human PDAC cells, Panc1. These findings were corroborated in primary tumor cell lines derived from KSC mice, providing compelling evidence that TGF-β signaling induces TGM2 expression, which in turn contributes to the initiation of PDAC in the KC mouse model of PDAC. Together, these data provide the first mechanistic evidence that TGM2 functions as a context-dependent effector in PDAC pathogenesis, being essential to tumor initiation but bypassed in advanced disease driven by loss of key tumor suppressors. As such, this discover could open up new opportunities for developing innovative therapeutic strategies to curb this devastating disease. Citation Format: Polina Wright, Parash Parajuli, Deanna Ward, Emma Cullen, Muhammad Akbar, Azeddine Atfi. Context-dependent role of TGM2 in Pancreatic Ductal Adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr A012.