High metabolic activity is a hallmark of cancers, including hepatocellular carcinoma (HCC). However, the molecular features of HCC with high metabolic activity contributing to clinical outcomes and the therapeutic implications of these characteristics are poorly understood. We aimed to define the features of HCC with high metabolic activity and uncover its association with response to current therapies. By integrating gene expression data from mouse liver tissues and tumor tissues from HCC patients (n = 1038), we uncovered three metabolically distinct HCC subtypes that differ in clinical outcomes and underlying molecular biology. The high metabolic subtype is characterized by poor survival, the strongest stem cell signature, high genomic instability, activation of EPCAM and SALL4, and low potential for benefitting from immunotherapy. Interestingly, immune cell analysis showed that regulatory T cells (Tregs) are highly enriched in high metabolic HCC tumors, suggesting that high metabolic activity of cancer cells may trigger activation or infiltration of Tregs, leading to cancer cells’ evasion of anti-cancer immune cells. In summary, we identified clinically and metabolically distinct subtypes of HCC, potential biomarkers associated with these subtypes, and a potential mechanism of metabolism-mediated immune evasion by HCC cells.

Hepatocellular carcinoma (HCC), the most common liver cancer, exhibits a higher incidence in males. Here, we report that mice lacking the bile acid regulators, Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and FXR and SHP double knockout livers identified female-specific changes in metabolism, including amino acids, lipids, and steroids. We examined if the obtained transcriptomic signatures correlate with the survival outcomes for HCC patients to assess the translational potential of this murine HCC model. Gene signatures that are unique to the knockout females correspond with low-grade tumors and better survival. Ovariectomy blunts the metabolic changes in female livers and promotes tumorigenesis that, intriguingly, coincides with increases in serum bile acid (BA) levels. Despite similar genetics, we found higher serum BA concentrations in males, whereas female knockout mice excreted more BAs. Decreasing enterohepatic BA recirculation using cholestyramine, an FDA-approved resin, dramatically reduced the liver cancer burden in male mice. Overall, we reveal that sex-specific BA metabolism leading to lower circulating BA concentration protects female livers from developing cancer. Thus, targeting BA excretion may be a promising therapeutic strategy against HCC. Significance: We show that female-specific gene profiles identified in Fxr ^-/- , Shp ^-/- double knockout (DKO) mice correlate with better outcomes for HCC patients and uncover sex differences in circulation and excretion of bile acid. Overall, we demonstrate that increasing (ovariectomy or chemical injury) or decreasing (pharmacologically with FDA-approved resin) serum bile acids, not hepatic bile acids, promoted or alleviated liver cancer burden.

Even though the current clinical staging system for resectable pancreatic cancer has validated major clinicopathologic factors in multiple clinical cohorts, there is still an unmet need for integrative consideration using multi-omics data to stratify the patients with pancreatic cancer elaborately. We performed a comprehensive analysis and profiling using genomic, transcriptomic, and proteomic data from TCGA-PAAD (n = 150) and other translational cohorts (4 cohorts, n = 340). Molecular features and major subtypes were analyzed mutually with clinical and pathologic factors to discover a clinically relevant translational staging system. The correlation analysis for each 50 cancer-specific molecular pathways with the clinical staging system revealed no remarkable pattern of the association. The mutational pattern of KRAS and several transcriptomic pathways, such as epithelial-mesenchymal transition and DNA repair, were differently presented in each clinical stage from the 8th AJCC TNM staging system. From the cluster of cluster analysis, we identified three consensus molecular subtypes, specifically subtype A was remarkably correlated with previously known aggressive subtypes, Basal, Mesenchymal, and Squamous subtypes, and subtype B and C were correlated with other subtypes regarding classical, exocrine, immunogenic, progenitor and ADEX subtypes. This consensus subtypes were validated at the independent pancreatic cancer genomics cohorts. Our in-silico prediction revealed subtype-specific biomarkers and potential therapeutics, including molecular target agents as well as immunotherapeutic options. Our comprehensive multi-omics analysis reveals prognostically significant consensus subtypes showing distinct tumor biology with unique therapeutic opportunities including biomarkers with high performance. This study provides exact needs for clinical trials based on translational approaches to establish precision surgical oncology.

Pancreatic cancer is a devastating disease with a high relapse rate, even in resectable pancreatic cancer. This study aimed to identify the prognostic significance and therapeutic chance of the metabolic subtypes for resectable pancreatic cancer. We obtained transcriptomic data from the TCGA-PAAD cohort via the The Cancer Genome Atlas (TCGA) data portal (n = 182). After integrative analysis of transcriptomic data in the discovery cohort, immunohistochemical (IHC) staining was performed in the independent cohort to validate the molecule of interest. Experimental testing for the molecule of interest was performed using pancreatic cancer cell lines, including AsPC1, BxPC3, MIA PaCa-2, and PANC-1 in vitro. Two subtypes showing distinct gene expression patterns in the TCGA-PAAD dataset were identified. The active glucose metabolism subtype showed significantly lower survival regarding cancer relapse after surgical resection. The genes SLC2A1 (GLUT1) and SLC16A3 (MCT4) were highly enriched in the active metabolism subtype. The validation cohort showed high IHC staining intensity for MCT4 and a significantly high relapse rate (p = 0.01). Several molecular pathways associated with aggressive tumor biology regarding cell cycle, Myc, and mTOR downstream signaling were highly enriched in the high glucose uptake subtype as well as distinct response for immunotherapy. MCT4 inhibition suppressed pancreatic cancer cell lines in vitro and showed a synergetic effect with gemcitabine treatment. MCT4 was identified from integrative analysis as a potential therapeutic target in resectable pancreatic cancer. The precision strategy for resectable pancreatic cancer should be validated in a clinical setting with a prospective study design.