TM4SF20 scaffolds DDR1-IRS4 signaling to drive PDAC metastasis and represents a druggable therapeutic target

Pancreatic ductal adenocarcinoma (PDAC) exhibits an exceptionally high propensity for liver metastasis, which critically contributes to its poor clinical outcomes. However, therapeutic strategies specifically targeting metastatic progression remain limited. In this study, we investigated the molecular mechanisms driving PDAC liver metastasis and explored therapeutic approaches capable of suppressing metastatic dissemination. Leveraging single-cell sequencing data from pancreatic cancer samples collected at our center, we identified transmembrane 4 L six family member 20 (TM4SF20), a tetraspanin-like transmembrane protein, as a previously unrecognized driver of metastatic progression. TM4SF20 is markedly upregulated in PDAC and highly enriched within liver metastatic lesions. Through integrative analyses combining clinical pathological data, TM4SF20-knockout mouse models, organoid systems, and multiple experimental platforms-including small-animal PET-CT, ultrasonography, immunoprecipitation-mass spectrometry, and in vitro kinase assays-we systematically validated the functional role of TM4SF20 in promoting PDAC liver metastasis. Mechanistically, TM4SF20 acts as a membrane “bridge molecule”: its extracellular domain binds discoidin domain receptor 1 (DDR1), while its intracellular domain interacts with insulin receptor substrate 4 (IRS4). This scaffolding enables DDR1-dependent phosphorylation of IRS4 at T208, thereby activating the AKT signaling cascade and enhancing invasive and metastatic phenotypes. Therapeutic blockade of TM4SF20 with a monoclonal antibody (alphaTM4SF20) disrupted DDR1-IRS4 complex formation, suppressed downstream signaling, and attenuated PDAC cell migration and invasion. Guided by this mechanistic insight, we developed a TM4SF20-directed antibody-drug conjugate (TM4SF20-ADC) by conjugating alphaTM4SF20 with the topoisomerase I inhibitor deruxtecan (DXD). TM4SF20-ADC retained high target specificity and exhibited potent antitumor activity, inducing apoptosis, depleting metastatic TM4SF20-positive cells, and markedly inhibiting tumor growth and liver metastasis. In orthotopic PDAC models with established liver metastases, TM4SF20-ADC simultaneously eliminated primary and metastatic lesions, significantly reducing tumor burden and extending survival without detectable systemic toxicity. Collectively, this study identifies TM4SF20 as a key metastatic driver and establishes TM4SF20-targeted ADC therapy as a promising translational strategy for PDAC liver metastasis.