TINAG suppresses renal cell carcinoma progression and angiogenesis by rebalancing mTORC1 signaling via integrin α3β1 receptor

Abstract The mammalian target of rapamycin (mTOR) signalling is crucial in promoting tumor growth and metastasis. Yet current mTOR inhibitors face limitations due to resistance and adverse effects. Inhibitors block the cytoplasmic signalling of mTOR, which may induce feedback loops that activate other cell proliferative signalling or reactivates mTOR itself, making it difficult to achieve complete inhibition of mTOR activities. In this study, we identified tubulointerstitial nephritis antigen (TINAG), a kidney-specific extracellular matrix protein, as an extracellular regulator of mTOR. Our data demonstrate that TINAG binds to integrin α3β1 transducing negative signals that suppress mTORC1 activity in tumor and endothelial cells, thereby reducing proliferation, migration, and angiogenesis. In both in vitro and in vivo models, TINAG protein exhibited pronounced inhibition on RCC growth and metastasis in wild-type RCC tumor and a sorafenib-resistant tumor model. Surprisingly, we also found the integrin α3β1 receptor with its canonical ligands did not promote cell growth, on the contrary, integrin α3β1 overexpression inhibited cell growth and migration. More interestingly, TINAG also exhibited an antiangiogenic potential, which functioned as a dual inhibitor on tumor cell and blood vessels simultaneously. Our finding reveals an extracellular mechanism regulating mTORC1 via TINAG-integrin interaction, suggesting TINAG as a novel tumor suppressor and promising dual targeting therapeutic candidate for RCC treatment.