Microenvironment and cell state, plasticity, and drug response in Hepatic and Biliary Cancer

Precision medicine is changing the approach to patients harboring neoplasms. The diversity of cancer in the gastrointestinal and hepatobiliary systems has evidenced that it can complicate the estimation of prognosis. The optimal timing and selection of treatment regimens for individual patients may be jeopardized. In colon-rectal cancer, pathological staging by tumor-node-metastasis (TNM), sidedness, and a few molecular markers, including mismatch repair (MMR), BRAF (B-Raf proto-oncogene serine/threonine kinase), and RAS (Kirsten rat sarcoma) mutation status, are usually used in clinical practice to identify patients for specific therapies. Recently, the BEACON drug regimen (encorafenib as BRAF-inhibitor, binimetinib as MAP2K-inhibitor or Mitogen-activated protein kinase kinase (also MEK), and cetuximab as anti-EGFR, anti-epithelial growth factor receptor) has been proposed to be effective for BRAF mutant metastatic colo-rectal cancer. The consensus molecular subtype (CMS) classification is a stratification strategy for colo-rectal cancer established because of differences in tumor biology rather than clinical outcomes. It captures the intrinsic biomolecular heterogeneity of colon-rectal cancer. It is based on differential gene expression in tumor tissue, encompassing both cancer cells as well as the microenvironment. Colon-rectal cancer can be divided into 4 subtypes (CMS1-4). CMS1 is the immunogenic subtype, enriched for MSI tumors and BRAF mutations. Epithelial characteristics with marked WNT (Wnt/β-Catenin signaling pathway) and MYC (Myelocytomatosis) signaling and high chromosomal instability (CIN) characterize CMS2. The CMS3 has epithelial features but less CIN. It is enriched for KRAS mutations, and occurs with evident metabolic dysregulation. Finally, the CMS4 is the mesenchymal subtype with prominent transforming growth factor beta (TGF-β) activation, stromal invasion, angiogenesis, and an inflammatory, immunosuppressive phenotype. Hepatocellular carcinoma can also be stratified into four distinct immune subtypes. Hepatocellular carcinoma with a high immune activation is characterized by high anti-tumor immunity accompanied with high cancer-related hallmark signatures. They include epithelial–mesenchymal transition, angiogenesis, and apoptosis. Autophagy-related proteins (Beclin-1, LAMP-1, LC3, and p62) and NanoString technology for gene expression have been used to pinpoint the microenvironment for the EBV-driven oncogenesis. The microenvironment of tumors is dynamic, with a variety of cell types and different molecular pathways at play, and studies may clearly warrant further investigation. In this special issue, we welcome papers addressing the tumor microenvironment and cell state, plasticity, and drug response in hepatic and biliary oncogenesis.