Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I–IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab.

Sensitive detection of protein interactions and post-translational modifications of native proteins is a challenge for research and diagnostic purposes. A method for this, which could be used in point-of-care devices and high-throughput screening, should be reliable, cost effective and robust. To achieve this, here we design a method (proxHCR) that combines the need for proximal binding with hybridization chain reaction (HCR) for signal amplification. When two oligonucleotide hairpins conjugated to antibodies bind in close proximity, they can be activated to reveal an initiator sequence. This starts a chain reaction of hybridization events between a pair of fluorophore-labelled oligonucleotide hairpins, generating a fluorescent product. In conclusion, we show the applicability of the proxHCR method for the detection of protein interactions and posttranslational modifications in microscopy and flow cytometry. As no enzymes are needed, proxHCR may be an inexpensive and robust alternative to proximity ligation assays.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. It can be caused by chronic liver cell injury with resulting sustained inflammation, e.g., triggered by infections with hepatitis viruses B (HBV) and C (HCV). Death of hepatocytes leads to the activation of compensatory mechanisms, which can ultimately result in liver fibrosis and cirrhosis. Another common feature is the infiltration of the liver with inflammatory cells, which secrete cytokines and chemokines that act directly on the hepatocytes. Among several secreted proteins, members of the interleukin-6 (IL-6) family of cytokines have emerged as important regulatory proteins that might constitute an attractive target for therapeutic intervention. The IL-6-type cytokines activate multiple intracellular signaling pathways, and especially the Jak/STAT cascade has been shown to be crucial for HCC development. In this review, we give an overview about HCC pathogenesis with respect to IL-6-type cytokines and the Jak/STAT pathway. We highlight the role of mutations in genes encoding several proteins involved in the cytokine/Jak/STAT axis and summarize current knowledge about IL-6 family cytokines in this context. We further discuss possible anti-cytokine therapies for HCC patients in comparison to already established therapies.

Significance: T cells recognize their targets via their T-cell receptors (TCRs), which in the case of CD8 ⁺ T cells bind to MHC-I:antigen complexes on the surface of target cells. Many cancer cells evade immune recognition and killing by down-regulating MHC-I AgPPM. Here, we show how the histone acetyl transferases p300/CBP together with NF-κB epigenetically regulate expression of MHC-I molecules, immunoproteasome subunits, and peptide transporter to enable proper MHC-I antigen presentation. Notably, this pathway is frequently disrupted in human cancers. We now show that certain chemotherapeutics can augment MHC-I antigen presentation via NF-κB and p300/CBP activation, thereby enhancing cancer cell recognition and killing by effector CD8 ⁺ CTLs.

Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related deaths and commonly develops in inflammatory environments. The IGF2 mRNA-binding protein IMP2-2/IGF2BP2-2/p62 was originally identified as an autoantigen in HCC. Aim of this study was to investigate a potential pathophysiological role of p62 in hepatocarcinogenesis. Human HCC tissue showed overexpression of IMP2, which strongly correlated with the fetal markers AFP and DLK1/Pref-1/FA-1 and was particularly elevated in tumors with stem-like features and hypervascularization. Molecular classification of IMP2-overexpressing tumors revealed an aggressive phenotype. Livers of mice overexpressing the IMP2 splice variant p62 highly expressed the stem cell marker DLK1 and secreted DLK1 into the blood. p62 was oncogenic: diethylnitrosamine (DEN)-treated p62 transgenic mice exhibited a higher tumor incidence and multiplicity than wild types. Tumors of transgenics showed a more aggressive and stem-like phenotype and displayed more oncogenic chromosomal aberrations determined with aCGH analysis. DEN-treated p62 transgenic mice exhibited distinct signs of inflammation, such as inflammatory cytokine expression and oxidative stress markers, that is, thiobarbituric acid-reactive substance (TBARS) levels. Reactive oxygen species (ROS) production was elevated in HepG2 cells, which either overexpressed p62 or were treated with DLK1. p62 induced this ROS production by a DLK1-dependent induction and activation of the small Rho-GTPase RAC1, activating NADPH oxidase and being overexpressed in human HCC. Our data indicate that p62/IMP2 promotes hepatocarcinogenesis by an amplification of inflammation.