Cancer genomics has enabled the exhaustive molecular characterization of tumors and exposed hepatocellular carcinoma (HCC) as among the most complex cancers. This complexity is paralleled by dozens of mouse models that generate histologically similar tumors but have not been systematically validated at the molecular level. Accurate models of the molecular pathogenesis of HCC are essential for biomedical progress; therefore we compared genomic and transcriptomic profiles of four separate mouse models [MUP transgenic, TAK1-knockout, carcinogen-driven diethylnitrosamine (DEN), and Stelic Animal Model (STAM)] with those of 987 HCC patients with distinct etiologies. These four models differed substantially in their mutational load, mutational signatures, affected genes and pathways, and transcriptomes. STAM tumors were most molecularly similar to human HCC, with frequent mutations in Ctnnb1 , similar pathway alterations, and high transcriptomic similarity to high-grade, proliferative human tumors with poor prognosis. In contrast, TAK1 tumors better reflected the mutational signature of human HCC and were transcriptionally similar to low-grade human tumors. DEN tumors were least similar to human disease and almost universally carried the Braf V637E mutation, which is rarely found in human HCC. Immune analysis revealed that strain-specific MHC-I genotype can influence the molecular makeup of murine tumors. Thus, different mouse models of HCC recapitulate distinct aspects of HCC biology, and their use should be adapted to specific questions based on the molecular features provided here.

The polymorphic nature and intrinsic instability of class I major histocompatibility complex (MHC-I) and MHC-like molecules loaded with suboptimal peptides, metabolites, or glycolipids presents a fundamental challenge for identifying disease-relevant antigens and antigen-specific T cell receptors (TCRs), hindering the development of autologous therapeutics. Here, we leverage the positive allosteric coupling between the peptide and light chain (β ₂ microglobulin, β ₂ m) subunits for binding to the MHC-I heavy chain (HC) through an engineered disulfide bond bridging conserved epitopes across the HC/β ₂ m interface, to generate conformationally stable, peptide-receptive molecules named “open MHC-I.” Biophysical characterization shows that open MHC-I molecules are properly folded protein complexes of enhanced thermal stability compared to the wild type when loaded with low- to moderate-affinity peptides. Using solution NMR, we characterize the effects of the disulfide bond on the conformation and dynamics of the MHC-I structure, ranging from local changes in β ₂ m-interacting sites of the peptide-binding groove to long-range effects on the α _2-1 helix and α ₃ domain. The interchain disulfide bond stabilizes MHC-I molecules in an open conformation to promote peptide exchange across multiple human leukocyte antigen (HLA) allotypes, covering representatives from five HLA-A supertypes, six HLA-B supertypes, and oligomorphic HLA-Ib molecules. Our structure-guided design, combined with conditional β-peptide ligands, provides a universal platform to generate ready-to-load MHC-I systems of enhanced stability, enabling a range of approaches to screen antigenic epitope libraries and probe polyclonal TCR repertoires covering highly polymorphic HLA-I allotypes, as well as oligomorphic nonclassical molecules.

The liver plays an outsized role in oncology. Liver tumors are one of the most frequently found tumors in cancer patients and these arise from either primary or metastatic disease. Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer and the 6th most common cancer type overall, is expected to become the 3rd leading cause of cancer mortality in the US by the year 2030. The liver is also the most common site of distant metastasis from solid tumors. For instance, colorectal cancer (CRC) metastasizes to the liver in two-thirds of cases, and CRC liver metastasis is the leading cause of mortality in these patients. The interplay between inflammation and cancer is unmistakably evident in the liver. In nearly every case, HCC is diagnosed in chronic liver disease (CLD) and cirrhosis background. The consumption of a Western-style high-fat diet is a major risk factor for the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), both of which are becoming more prevalent in parallel with the obesity epidemic. Excessive alcohol intake also contributes significantly to the CLD burden in the form of alcoholic liver disease (ALD). Inflammation is a key component in the development of all CLDs. Additionally, during the development of liver metastasis, pro-inflammatory signaling is crucial in eliminating invading cancer cells but ironically also helps foster a pro-metastatic environment that supports metastatic seeding and colonization. Here we review how Westernized high-fat diets and excessive alcohol intake can influence inflammation within the liver microenvironment, stimulating both primary and metastatic liver tumorigenesis.

The liver has remarkable regenerative capacity owing to the boundless proliferative potential of hepatocytes. During liver injury, sustained regeneration must be balanced by mechanisms limiting overgrowth and tumorigenesis. Epithelial plasticity is frequently observed during liver damage and is thought to mediate production of biliary epithelial cells (BECs) or hepatocytes, depending on tissue needs. Here we show that hepatocytes persisting in plastic states are present in virtually all liver injury contexts, representing the predominant outcome of hepatocyte reprogramming rather than their full BEC conversion. By developing tools to trap mouse hepatocytes in plastic states in vivo and using models of regeneration and transplantation, we show that plastic hepatocytes are refractory to proliferation cues from the microenvironment. Unlike terminally differentiated hepatocytes, plastic hepatocytes resist proliferation driven by endogenous oncogenic stimuli. Thus, acquisition of plastic states represents a protective mechanism that constrains hepatocyte proliferation, limiting overgrowth and tumorigenesis during liver disease.

MHC-I exposes the intracellular contents to immune cells for surveillance of cellular health. Due to high genomic variation, individuals' immune systems differ in their ability to expose and eliminate cancer-causing mutations. These personalized immune blind spots create specific oncogenic mutation predispositions within patients and influence their prevalence across populations.