Noncanonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma

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Abstract

Hepatocellular carcinoma (HCC) is heterogeneous, and hepatocyte plasticity is linked to poorer patient outcomes. A subset of human HCC harboring tuberous sclerosis complex 1 (TSC1) mutations exhibits more aggressive behavior. Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and cell fate. We analyzed human normal and HCC tissue arrays for TFEB and CK19 expression, as well as bulk and single-cell RNA-seq datasets from mouse and human HCC, to define TFEB-associated transcriptional programs. We performed biochemical, histological, metabolomic, and transcriptomic analyses in liver-specific Tsc1-knockout (L-Tsc1–KO) and L-Tsc1 Tfeb–double KO mice. Loss of hepatic Tsc1 led to increased phosphorylation of S6 and 4EBP1, with paradoxical increases in TFEB nuclear translocation and activation. L-Tsc1–KO mice showed increased hepatocyte plasticity, decreased HNF4α, increased YAP activation, and spontaneous HCC with increased SOX9- and CK19-positive biliary epithelial cell–like cells at 8–12 months. Deletion of Tfeb dampened hepatic metabolic reprogramming and hepatocyte fate changes and inhibited tumor progression in L-Tsc1–KO mice. Increased TFEB activity was associated with increased YAP and SOX9 gene expression and high-grade malignant HCC in humans. These findings indicate that loss of hepatic TSC1 leads to noncanonical TFEB activation, promoting hepatocyte plasticity and tumor heterogeneity associated with high-grade malignancy in both mouse and human HCC.

Authors

Chen Zhang, Xiaojuan Chao, Sha Neisha Williams, Xiaoli Wei, Anthony M. DiGirolamo, Alisha Bajracharya, Lichun Ma, Ming Huang, Nicholas Dunn, Wanqing Liu, Kaito Ueda, Masayuki Sugimoto, Andrea Ballabio, Hong-Min Ni, Wen-Xing Ding