Welcome Remarks

Tai-Lung ChaTaiwan Speaker Novel Target for GU Cancer Metastasis and TherapeuticsCancer progression is shaped by both cell-intrinsic adaptations and complex extrinsic interactions within the tumor microenvironment (TME). Here, we identify a transmembrane protein, Meta1, as a shared therapeutic target that exhibits a Janus-like role: promoting malignant phenotypes in cancer cells while restraining tumor-supportive functions in non-cancerous stromal and immune cells. Meta1 is expressed in both compartments of the TME, orchestrating a dual program that supports metastasis and immune evasion. Mechanistically, we uncovered a malignancy-promoting factor (MPF) that acts as a functional ligand for Meta1, selectively enhancing pro-invasive signaling in cancer cells. We further identify Meta1 as an unconventional G protein–coupled receptor (GPCR) that plays as an accelerator in cancer cells of the TME. Meta1 interacts with Rho-GDI and Gαq to activate RhoA-mediated cytoskeletal remodeling and amoeboid migration, facilitating metastatic dissemination. We further identify MPF binding to Meta1 initiates Gβγ signaling, elevating intracellular cAMP and activating Rap1, thereby amplifying cell motility and metastatic potential. Leveraging the Meta1–MPF interaction, we designed MPF-derived peptides that specifically bind Meta1 and serve as the basis for a novel peptide-based PROTAC, which efficiently induces degradation of Meta1 and abrogates its pro-metastatic functions. Our study unveils Meta1 as an atypical GPCR with canonical signaling capacity and topological divergence, representing a shared and targetable vulnerability that bridges cancer cell-intrinsic adaptation with extrinsic TME communication. These findings establish the Meta1–MPF axis as a compelling therapeutic target for suppressing metastasis and reprogramming the TME.