Portal hypertension is a central feature of chronic liver disease and a major driver of hepatocellular carcinoma (HCC) progression, independent of the severity of the underlying liver disease. Transjugular intrahepatic portosystemic shunt (TIPS), and more broadly portosystemic shunting, profoundly decreases portal pressure and remodels hepatic hemodynamics. However, its impact on HCC biology remains poorly understood.
This three-year work investigated the interplay between portosystemic shunt physiology and HCC tumor progression through clinical and experimental approaches.
We first analyzed the Scientific Registry of Transplant Recipients (SRTR), a large prospective U.S. cohort of patients awaiting liver transplantation. Comparison of HCC dynamics between TIPS and non-TIPS patients revealed that TIPS was associated with improved overall survival before transplantation, without increasing the risk of tumor recurrence after transplantation. While waiting for transplantation, patients with TIPS displayed a decreased nodule count and stable alpha-fetoprotein changes, suggesting a relative stabilization of tumor burden under portal decompression.
To validate these observations at the molecular level, we studied tumor RNA sequencing data from a matched institutional cohort from Tours, France. These analyses uncovered immune activation signatures and differentially expressed genes related to tumor metabolism in favor of TIPS patients, providing mechanistic insights into how portosystemic shunting may modulate tumor biology.
Building on this, we studied a MASLD mouse model of HCC with surgical portosystemic shunting. Phenotypically, shunted mice developed larger tumors compared with controls. Transcriptomic profiling of their tumors revealed profound metabolic rewiring favoring tumor growth.
Complementary ad hoc analyses of MASLD patients within the SRTR cohort confirmed these experimental mouse findings. We evidenced enhanced tumor growth in TIPS patients, and this new observation contrasts with the use of TIPS depending on the underlying liver disease.
Eventually, these findings demonstrate that portosystemic shunting, whether surgical or by TIPS, exerts profound and complex effects on HCC biology. By altering tumor metabolism and tumor immunity, shunting reshapes the transcriptomic landscape of HCC. This raises critical clinical questions regarding patient selection for TIPS, especially in MASLD candidates.
