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A 42-year-old man was admitted to the intensive care unit in October 2020 for coronavirus disease-19 (COVID-19)-related acute respiratory distress syndrome requiring mechanical ventilation. He presented with multi-organ failure and died 41 days later. Comorbidities included a sleeve gastrectomy in 2016 and cholecystectomy in April 2020. Autopsy revealed difuse alveolar damage (Fig. 1A) and presence of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) in the carotid body (Fig. 1B, C). Detection of SARS-CoV-2 in the carotid body was performed by real-time reverse transcription polymerase chain reaction (Fig. 1D).

BackgroundHigh-mobility group box 1 (HMGB1) is a multifunctional redox-sensitive protein involved in various intracellular (eg, chromatin remodeling, transcription, autophagy) and extracellular (inflammation, autoimmunity) processes. Regarding its role in cancer development/progression, paradoxical results exist in the literature and it is still unclear whether HMGB1 mainly acts as an oncogene or a tumor suppressor.MethodsHMGB1 expression was first assessed in tissue specimens (n=359) of invasive breast, lung and cervical cancer and the two distinct staining patterns detected (nuclear vs cytoplasmic) were correlated to the secretion profile of malignant cells, patient outcomes and the presence of infiltrating immune cells within tumor microenvironment. Using several orthotopic, syngeneic mouse models of basal-like breast (4T1, 67NR and EpRas) or non-small cell lung (TC-1) cancer, the efficacy of several HMGB1 inhibitors alone and in combination with immune checkpoint blockade antibodies (anti-PD-1/PD-L1) was then investigated. Isolated from retrieved tumors, 14 immune cell (sub)populations as well as the activation status of antigen-presenting cells were extensively analyzed in each condition. Finally, the redox state of HMGB1 in tumor-extruded fluids and the influence of different forms (oxidized, reduced or disulfide) on both dendritic cell (DC) and plasmacytoid DC (pDC) activation were determined.ResultsAssociated with an unfavorable prognosis in human patients, we clearly demonstrated that targeting extracellular HMGB1 elicits a profound remodeling of tumor immune microenvironment for efficient cancer therapy. Indeed, without affecting the global number of (CD45+) immune cells, drastic reductions of monocytic/granulocytic myeloid-derived suppressor cells (MDSC) and regulatory T lymphocytes, a higher M1/M2 ratio of macrophages as well as an increased activation of both DC and pDC were continually observed following HMGB1 inhibition. Moreover, blocking HMGB1 improved the efficacy of anti-PD-1 cancer monoimmunotherapy. We also reported that a significant fraction of HMGB1 encountered within cancer microenvironment (interstitial fluids) is oxidized and, in opposite to its reduced isoform, oxidized HMGB1 acts as a tolerogenic signal in a receptor for advanced glycation endproducts-dependent manner.ConclusionCollectively, we present evidence that extracellular HMGB1 blockade may complement first-generation cancer immunotherapies by remobilizing antitumor immune response.

Breast cancer is a leading malignancy affecting the female population worldwide. Most morbidity is caused by metastases that remain incurable to date. TGF-β1 has been identified as a key driving force behind metastatic breast cancer, with promising therapeutic implications. Employing immunohistochemistry (IHC) analysis, we report, to our knowledge for the first time, that asporin is overexpressed in the stroma of most human breast cancers and is not expressed in normal breast tissue. In vitro, asporin is secreted by breast fibroblasts upon exposure to conditioned medium from some but not all human breast cancer cells. While hormone receptor (HR) positive cells cause strong asporin expression, triple-negative breast cancer (TNBC) cells suppress it. Further, our findings show that soluble IL-1β, secreted by TNBC cells, is responsible for inhibiting asporin in normal and cancer-associated fibroblasts. Using recombinant protein, as well as a synthetic peptide fragment, we demonstrate the ability of asporin to inhibit TGF-β1-mediated SMAD2 phosphorylation, epithelial to mesenchymal transition, and stemness in breast cancer cells. In two in vivo murine models of TNBC, we observed that tumors expressing asporin exhibit significantly reduced growth (2-fold; p = 0.01) and metastatic properties (3-fold; p = 0.045). A retrospective IHC study performed on human breast carcinoma (n = 180) demonstrates that asporin expression is lowest in TNBC and HER2+ tumors, while HR+ tumors have significantly higher asporin expression (4-fold; p = 0.001). Assessment of asporin expression and patient outcome (n = 60; 10-y follow-up) shows that low protein levels in the primary breast lesion significantly delineate patients with bad outcome regardless of the tumor HR status (area under the curve = 0.87; 95% CI 0.78-0.96; p = 0.0001). Survival analysis, based on gene expression (n = 375; 25-y follow-up), confirmed that low asporin levels are associated with a reduced likelihood of survival (hazard ratio = 0.58; 95% CI 0.37-0.91; p = 0.017). Although these data highlight the potential of asporin to serve as a prognostic marker, confirmation of the clinical value would require a prospective study on a much larger patient cohort. Our data show that asporin is a stroma-derived inhibitor of TGF-β1 and a tumor suppressor in breast cancer. High asporin expression is significantly associated with less aggressive tumors, stratifying patients according to the clinical outcome. Future pre-clinical studies should consider options for increasing asporin expression in TNBC as a promising strategy for targeted therapy.

As the primary etiological agents of cervical cancer, human papillomaviruses (HPVs) must deliver their genetic material into the nucleus of the target cell. The viral capsid has evolved to fulfil various roles that are critical to establish viral infection. The particle interacts with the cell surface via interaction of the major capsid protein, L1, with heparan sulfate proteoglycans. Moreover, accumulating evidence suggests the involvement of a secondary receptor and a possible role for the minor capsid protein, L2, in cell surface interactions. The entry of HPV in vitro is initiated by binding to a cell surface receptor in contrast to the in vivo situation where the basement membrane has recently been identified as the primary site of virus binding. Binding of HPV triggers conformational changes, which affect both capsid proteins L1 and L2, and such changes are a prerequisite for interaction with the elusive uptake receptor. Most HPV types that have been examined, appear to enter the cell via a clathrin-dependent endocytic mechanism, although many data are inconclusive and inconsistent. Furthermore, the productive entry of HPV is a process that occurs slowly and asynchronously and it is characterised by an unusually extended residence on the cell surface. Despite the significant advances and the emergence of a general picture of the infectious HPV entry pathway, many details remain to be clarified. The impressive technological progress in HPV virion analysis achieved over the past decade, in addition to the improvements in general methodologies for studying viral infections, provide reasons to be optimistic about further advancement of this field. This mini review is intended to provide a concise overview of the literature in HPV virion/host cell interactions and the consequences for endocytosis.

Cancer-associated fibroblasts (CAF) are important constituents of the tumor microenvironment (TME) and are major drivers of tumorigenesis. Yet, therapies aiming at eliminating CAF have failed to cure patients. This setback has raised questions regarding whether CAF exclusively favour cancer progression, or if they may also assume tumor-suppressor functions. In the present study, we used proteomics and single cell RNA-sequencing analysis to examine the CAF landscape in hepatocellular carcinoma (HCC). We thereby unveil three major CAF populations in HCC, one of which specifically expressing the prolargin protein. This CAF subpopulation (further termed as CAF_Port) shared a strong transcriptomic signature with portal liver fibroblasts. We further show that CAF_Port deposit prolargin in the TME and that its levels are lower in tumors as compared to the peritumoral region. Mechanistically, aggressive cancer cells degraded prolargin using matrix metalloprotease activity. Survival analysis of 188 patients revealed that high prolargin protein levels correlate with good patient outcome (HR = 0.37; p  = 0.01). In vivo, co-injection of cancer cells with fibroblasts silenced for prolargin, led to faster tumor development (5-fold; p  = 0.01), mainly due to stronger angiogenesis. Using protein-protein interaction study and structural modelling, we further demonstrate that prolargin binds and inhibits the activity of several pro-agiogenic proteins, including hepatocyte and fibroblast growth factors. In conclusion, prolargin is angiogenesis modulator and CAF-derived tumor suppressor in HCC. Stabilizing prolargin levels in the CAF_Port subpopulation may revert their tumor-antagonizing properties, warranting exploration in further pre-clinical studies.

The integration of a viral genome into the host genome has a major impact on the trajectory of the infected cell. Integration location and variation within the associated viral genome can influence both clonal expansion and persistence of infected cells. Methods based on short-read sequencing can identify viral insertion sites, but the sequence of the viral genomes within remains unobserved. We develop PCIP-seq, a method that leverages long reads to identify insertion sites and sequence their associated viral genome. We apply the technique to exogenous retroviruses HTLV-1, BLV, and HIV-1, endogenous retroviruses, and human papillomavirus.

Background Elevated aerobic glycolysis rate is a biochemical alteration associated with malignant transformation and cancer progression. This metabolic shift unavoidably generates methylglyoxal (MG), a potent inducer of dicarbonyl stress through the formation of advanced glycation end products (AGEs). We have previously shown that the silencing of glyoxalase 1 (GLO1), the main MG detoxifying enzyme, generates endogenous dicarbonyl stress resulting in enhanced growth and metastasis in vivo. However, the molecular mechanisms through which MG stress promotes metastasis development remain to be unveiled. Methods In this study, we used RNA sequencing analysis to investigate gene-expression profiling of GLO1-depleted breast cancer cells and we validated the regulated expression of selected genes of interest by RT-qPCR. Using in vitro and in vivo assays, we demonstrated the acquisition of a pro-metastatic phenotype related to dicarbonyl stress in MDA-MB-231, MDA-MB-468 and MCF7 breast cancer cellular models. Hyperactivation of MEK/ERK/SMAD1 pathway was evidenced using western blotting upon endogenous MG stress and exogenous MG treatment conditions. MEK and SMAD1 regulation of MG pro-metastatic signature genes in breast cancer cells was demonstrated by RT-qPCR. Results High-throughput transcriptome profiling of GLO1-depleted breast cancer cells highlighted a pro-metastatic signature that establishes novel connections between MG dicarbonyl stress, extracellular matrix (ECM) remodeling by neoplastic cells and enhanced cell migration. Mechanistically, we showed that these metastasis-related processes are functionally linked to MEK/ERK/SMAD1 cascade activation in breast cancer cells. We showed that sustained MEK/ERK activation in GLO1-depleted cells notably occurred through the down-regulation of the expression of dual specificity phosphatases in MG-stressed breast cancer cells. The use of carnosine and aminoguanidine, two potent MG scavengers, reversed MG stress effects in in vitro and in vivo experimental settings. Conclusions These results uncover for the first time the key role of MG dicarbonyl stress in the induction of ECM remodeling and the activation of migratory signaling pathways, both in favor of enhanced metastatic dissemination of breast cancer cells. Importantly, the efficient inhibition of mitogen-activated protein kinase (MAPK) signaling using MG scavengers further emphasizes the need to investigate their therapeutic potential across different malignancies.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic pathology in Western countries. It encompasses a spectrum of conditions ranging from simple steatosis to more severe and progressive non-alcoholic steatohepatitis (NASH) that can lead to hepatocellular carcinoma (HCC). Obesity and related metabolic syndrome are important risk factors for the development of NAFLD, NASH and HCC. DUSP3 is a small dual-specificity protein phosphatase with a poorly known physiological function. We investigated its role in metabolic syndrome manifestations and in HCC using a mouse knockout (KO) model. While aging, DUSP3-KO mice became obese, exhibited insulin resistance, NAFLD and associated liver damage. These phenotypes were exacerbated under high fat diet (HFD). In addition, DEN administration combined to HFD led to rapid HCC development in DUSP3-KO compared to wild type (WT) mice. DUSP3-KO mice had more serum triglycerides, cholesterol, AST and ALT compared to control WT mice under both regular chow diet (CD) and HFD. The level of fasting insulin was higher compared to WT mice, though, fasting glucose as well as glucose tolerance were normal. At the molecular level, HFD led to decreased expression of DUSP3 in WT mice. DUSP3 deletion was associated with increased and consistent phosphorylation of the insulin receptor (IR) and with higher activation of the downstream signaling pathway. In conclusion, our results support a new role for DUSP3 in obesity, insulin resistance, NAFLD and liver damage.

Despite the increasing use of humanized mouse models to study new approaches of graft-versus-host disease (GVHD) prevention, the pathogenesis of xenogeneic GVHD (xGVHD) in these models remains misunderstood. The aim of this study is to describe this pathogenesis in NOD/LtSz-Prkdc IL2rγ (NSG) mice infused with human PBMCs and to assess the impact of the expression of HLA-A0201 by NSG mice cells (NSG-HLA-A2/HHD mice) on xGVHD and graft-versus-leukemia (GvL) effects, by taking advantage of next-generation technologies. We found that T cells recovered from NSG mice after transplantation had upregulated expression of genes involved in cell proliferation, as well as in TCR, co-stimulatory, IL-2/STAT5, mTOR and Aurora kinase A pathways. T cells had mainly an effector memory or an effector phenotype and exhibited a Th1/Tc1-skewed differentiation. TCRβ repertoire diversity was markedly lower both in the spleen and lungs (a xGVHD target organ) than at infusion. There was no correlation between the frequencies of specific clonotypes at baseline and in transplanted mice. Finally, expression of HLA-A0201 by NSG mice led to more severe xGVHD and enhanced GvL effects toward HLA-A2 leukemic cells. Altogether our data demonstrate that the pathogenesis of xGVHD shares important features with human GVHD and that NSG-HLA-A2/HHD mice could serve as better model to study GVHD and GvL effects.

Accounting for 15–30% of colorectal cancer cases, the serrated pathway remains poorly characterized compared to the adenoma–carcinoma sequence. It involves sessile serrated lesions as precursors and is characterized by BRAF mutations (BRAFV600E), CpG island hypermethylation, and microsatellite instability (MSI). Using label-free proteomics, we compared normal tissue margins from patients with diverticular disease, sessile serrated lesions, low-grade adenomas, and high-grade adenomas. We identified S100A14 as significantly overexpressed in sessile serrated lesions compared to low-grade adenomas, high-grade adenomas, and normal tissues. This overexpression was confirmed by immunohistochemical scoring in an independent cohort. Gene expression analyses of public datasets showed higher S100A14 expression in BRAFV600E-mutated and MSI-H colorectal cancers compared to microsatellite stable BRAFwt tumors. This finding was confirmed by immunohistochemical scoring in an independent colorectal cancer cohort. Furthermore, single-cell RNA sequencing analysis from the Human Colon Cancer Atlas revealed that S100A14 expression in tumor cells positively correlated with the abundance of tumoral CD8+ cytotoxic T cells, particularly the CD8+ CXCL13+ subset, known for its association with a favorable response to immunotherapy. Collectively, our results demonstrate for the first time that S100A14 is a potential biomarker of serrated neoplasia and further suggests its potential role in predicting immunotherapy responses in colorectal cancer.