Role of hormone cofactors in the human papillomavirus-induced carcinogenesis of the uterine cervix

peer reviewedIf human papillomavirus (HPV) is necessary for the development of (pre)neoplastic lesions of the uterine cervix, it is not sufficient. Among the cofactors involved in the malignant transformation of cells infected by HPV, sex hormones may facilitate the cervical carcinogenesis by different mechanisms, including the induction of squamous metaplasia in the transformation zone of the cervix, interactions between steroid hormones and HPV gene expression and alterations of the local immune microenvironment

Characterisation of methylglyoxal stress in human colorectal cancer and liver metastases using immunohistochemistry.

Background: Glycolysis is the principal source of energy for cancerous cells. One inevitable consequence of the elevated glycolytic rate is the production of highly reactive molecules such as methylglyoxal (MG). MG induces the glycation of proteins on lysine and arginine residues and generates protein adducts called MG-derived hydroimidazolones (MGHs). Glyoxalase 1 (GLO1) is the main detoxifying enzyme of MG. It is expressed in most eukaryotes and prokaryotes and is localized in the cytoplasmic compartment. An increase of GLO1 expression and activity is a cell defence mechanism against glycation damage induced under MG stress. Our previous studies reported the presence of MG protein adducts in CRC tumours and have linked MG stress with the resistance to targeted therapy in KRAS-mutated CRCs. Aims: In this pilot project, we undertook the detection of MG stress in human CRC primary tumours and liver metastases lesions. Methods: We have used immunohistochemistry and antibodies directed against MGHs protein adducts and GLO1 enzyme in CRC samples. Specific Ki67 antibodies were used for the evaluation of tumour proliferation rate. Results: By comparison of the same histological sample for GLO1 and Ki67 immunostainings, we observed that GLO1 enzyme was strongly detectable in the nucleus of undifferentiated and highly proliferative human CRC lesions. While most of the well-differentiated CRC tumours demonstrated undetectable to low nuclear GLO1 levels in the nucleus. Cytoplasmic GLO1 was similarly distributed among differentiated and non-differentiated tumours. Conclusion: It might be therefore interesting to explore further this peculiar GLO1 sub-localisation that could potentially indicate for the first time the presence of MG stress in the nucleus and the necessity for the nuclear translocation of GLO1 detoxifying enzyme in aggressive CRC lesions. Whether nuclear GLO1 detection could be a valuable marker in terms of unfavourable prognosis in CRC patients will be analysed on a large collection of CRC patients with documented clinical data and follow-up

A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine.

Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. In this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed. Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa. Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits

Myoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by 18F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism

Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma

Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive bioma ricers are needed for better patient stratification and for the identification of new therapeutic strategies, including enhancing the efficacy of chemotoxic agents. Here, we hypothesized that discoidin domain receptor 1 (DDR1) may be both a predictive factor for chemoresistance in patients with LUAD and a potential target positively selected in resistant cells. By using biopsies from patients with LUAD, KRAS-mutant LUAD cell lines, and in vivo genetically engineered KRAS-driven mouse models, we evaluated the role of DDR1 in the context of chemotherapy treatment. We found that DORT is upregulated during chemotherapy both in vitro and in viva. Moreover, analysis of a cohort of patients with LUAD suggested that high DOR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DORI inhibition with chemotherapy prompted a synergistic therapeutic effect and enhanced cell death of KRAS-mutant tumors in vivo. Collectively, this study suggests a potential role for DDR1 as both a predictive and prognostic biomarker, potentially improving the chemotherapy response of patients with LUAD