TMOD3 drives malignant progression in pancreatic cancer through physical interaction with LRRFIP1

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by rapid progression and early metastasis. Although Tropomodulin 3 (TMOD3) regulates cytoskeletal dynamics, its clinical significance and molecular mechanisms in PDAC remain unclear. Here, we investigated the oncogenic role of TMOD3 in PDAC using the GEPIA database, a human tissue microarray, in vitro functional assays, and in vivo models of tumor growth and metastasis. We found that TMOD3 is significantly upregulated in PDAC tissues, correlating strongly with advanced tumor stage and poor overall survival. Functionally, TMOD3 knockdown markedly inhibited PDAC cell proliferation, migration, and invasion in vitro , and suppressed tumorigenicity and lung metastasis in vivo . Mechanistically, STRING prediction and endogenous co-immunoprecipitation revealed that TMOD3 physically interacts with Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1) without altering its transcription. Furthermore, rescue experiments demonstrated that silencing LRRFIP1 effectively abrogated TMOD3-induced malignant phenotypes and tumor growth both in vitro and in vivo . Collectively, our findings demonstrate that the TMOD3/LRRFIP1 axis drives PDAC progression and metastasis, highlighting TMOD3 as a promising prognostic biomarker and therapeutic target. Significance The high lethality of pancreatic cancer urgently requires the identification of novel therapeutic targets. This study is the first to reveal that TMOD3 strongly drives tumor proliferation and metastasis by physically interacting with LRRFIP1. Elucidating this novel TMOD3/LRRFIP1 oncogenic axis provides a promising prognostic biomarker and a compelling rationale for targeted interventions.