The Tumor Coagulome as a Transcriptional Target and a Potential Effector of Glucocorticoids in Human Cancers

Background: The coagulome, defined as the repertoire of genes that locally regulate coagulation and fibrinolysis, is a key determinant of vascular thromboembolic complications of cancer. In addition to vascular complications, the coagulome may also regulate the tumor microenvironment (TME). Glucocorticoids are key hormones that mediate cellular responses to various stresses and exert anti-inflammatory effects. We addressed the effects of glucocorticoids on the coagulome of human tumors by investigating interactions with Oral Squamous Cell Carcinoma, Lung Adenocarcinoma, and Pancreatic Adenocarcinoma tumor types. Methods: We analyzed the regulation of three essential coagulome components, i.e., the tissue factor (TF), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1) in cancer cell lines exposed to specific agonists of the glucocorticoid receptor (GR) (dexamethasone and hydrocortisone). We used QPCR, immunoblots, small-interfering RNA, Chromatin immunoprecipitation sequencing (ChIPseq) and genomic data from whole tumor and single-cell analyses. Results: Glucocorticoids modulate the coagulome of cancer cells through a combination of indirect and direct transcriptional effects. Dexamethasone directly increased PAI-1 expression in a GR-dependent manner. We confirmed the relevance of these findings in human tumors, where high GR activity/high SERPINE1 expression corresponded to a TME enriched in active fibroblasts and with a high TGF-β response. Conclusion: The transcriptional regulation of the coagulome by glucocorticoids that we report may have vascular consequences and account for some of the effects of glucocorticoids on the TME.</p

Evaluation of Proton MR Spectroscopy for the Study of the Tongue Tissue in Healthy Subjects and Patients With Tongue Squamous Cell Carcinoma: Preliminary Findings

PurposeTo noninvasively assess spectroscopic and metabolic profiles of healthy tongue tissue and in an exploratory objective in nontreated and treated patients with tongue squamous cell carcinoma (SCC).MethodsFourteen healthy subjects (HSs), one patient with nontreated tongue SCC (NT-SCC), and two patients with treated tongue SCC (T-SCC) underwent MRI and single-voxel proton magnetic resonance spectroscopy (1H-MRS) evaluations (3 and 1.5T). Multi-echo-times 1H-MRS was performed at the medial superior part (MSP) and the anterior inferior part (AIP) of the tongue in HS, while 1H-MRS voxel was placed at the most aggressive part of the tumor for patients with tongue SCC. 1H-MRS data analysis yielded spectroscopic metabolite ratios quantified to total creatine.ResultsIn HS, compared to MSP and AIP, 1H-MRS spectra revealed higher levels of creatine, a more prominent and well-identified trimethylamine-choline (TMA-Cho) peak. However, larger prominent lipid peaks were better differentiated in the tongue MSP. Compared to HS, patients with NT-SCC exhibited very high levels of lipids and relatively higher values of TMA-Cho peak. Interestingly, patients with T-SCC showed almost nonproliferation activity. However, high lipids levels were measured, although they were relatively lower than lipids levels measured in patients with NT-SCC.ConclusionThe present study demonstrated the potential use of in-vivo1H-MRS to noninvasively assess spectroscopic and metabolic profiles of the healthy tongue tissue in a spatial location-dependent manner. Preliminary results revealed differences between HS and patients with tongue NT-SCC as well as tongue T-SCC, which should be confirmed with more patients. 1H-MRS could be included, in the future, in the arsenal of tools for treatment response evaluation and noninvasive monitoring of patients with tongue SCC

Human antimicrobial protein hCAP18/LL-37 promotes a metastatic phenotype in breast cancer

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Title Page Agonists and allosteric modulators of the Calcium Sensing Receptor and their therapeutic applications MOL #58784 2 Running title page Running title: Agonists and allosteric modulators of the CaR

Words in abstract: 250 Abbreviations: ADH: autosomal dominant hypocalcemia; AGAs: aminoglycoside antibiotics; Ca Abstract The Calcium sensing Receptor (CaR) belongs to the G protein-coupled receptor superfamily, with a characteristic structure consisting of seven transmembrane helices, an intracellular C terminal and an extracellular N terminal domain. The primary physiological function of the CaR is the maintenance of constant blood Ca 2+ levels, due to its ability to sense very small changes in extracellular Ca 2

Agonists and allosteric modulators of the calcium-sensing receptor and their therapeutic applications. Mol Pharmacol 76

ABSTRACT The calcium-sensing receptor (CaR) belongs to the G proteincoupled receptor superfamily, with a characteristic structure consisting of seven transmembrane helices, an intracellular C-terminal and an extracellular N terminal domain

Coagulome and the tumor microenvironment: an actionable interplay

International audienceHighlights- A hypercoagulable state established within the tumor accounts for the frequent hemostatic complications that occur in cancer patients, including venous thromboembolism.- The coagulation cascades exert multiple direct and indirect effects on cancer cells and the components of the tumor microenvironment, both within and outside of the vascular space.- The recent application of systems biology and single-cell approaches provides a comprehensive and deeper view of the coagulome and highlights its link to the tumor microenvironment.- The study of the coagulome provides unprecedented opportunities to explore the tumor microenvironment, to better predict the hemostatic complications, revisit the significance of clinical biomarkers, and it might ultimately enable us to steer the tumor immune response or vascular integrity.Human tumors often trigger a hypercoagulable state that promotes hemostatic complications, including venous thromboembolism. The recent application of systems biology to the study of the coagulome highlighted its link to shaping the tumor microenvironment (TME), both within and outside of the vascular space. Addressing this link provides the opportunity to revisit the significance of biomarkers of hemostasis and assess the communication between vasculature and tumor parenchyma, an important topic considering the advent of immune checkpoint inhibitors and vascular normalization strategies. Understanding how the coagulome and TME influence each other offers exciting new prospects for predicting hemostatic complications and boosting the effectiveness of cancer treatment

La modélisation mathématique, un outil essentiel pour l’étude du ciblage thérapeutique des tumeurs solides

Les progrès de la décennie passée ont rendu l’étude du traitement médical des cancers plus efficace, mais ils ont aussi révélé la complexité des mécanismes de la cancérogenèse. Pour la plupart des tumeurs humaines, on connaît plusieurs cibles thérapeutiques et des médicaments potentiels. Malheureusement, les acteurs identifiés comme des cibles thérapeutiques fonctionnent en effet souvent en réseaux, ce qui engendre des suppléances fonctionnelles et des propriétés de résilience/résistance au ciblage thérapeutique. Le recours à la modélisation mathématique permet de réaliser des études de système dans l’optique d’améliorer le ciblage thérapeutique des tumeurs solides. Nous présentons les principaux types de modèles mathématiques et des exemples récents illustrant leur intérêt en oncobiologie moléculaire

ASO Visual Abstract: Contribution of Genomics to the Surgical Management and Study of Oral Cancer

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Contribution of Genomics to the Surgical Management and Study of Oral Cancer

International audienceBackground Oral squamous cell carcinoma (OSCC) is the most frequent type of tumor arising from the oral cavity. Surgery is the cornerstone of the treatment of these cancers. Tumor biology has long been overlooked as an important contributor to the outcome of surgical procedures, but recent studies are challenging this concept. Molecular analyses of tumor DNA or RNA provide a rich source of information about the biology of OSCC. Methods We searched for relevant articles using PubMed. We examined in particular the prospect of applying molecular methods for minimally invasive exploration of OSCC biology. Results We examined five potential applications of genomics to the surgical management and study of OSCC: i) assessing oral potentially malignant lesions; ii) tumor staging prior to surgery; iii) predicting postoperative risk in locally advanced tumors; iv) measuring minimal residual disease and optimizing the longitudinal monitoring of OSCC; and v) predicting the efficacy of medical treatment. Conclusions Genomic information can be harnessed in order to identify new biomarkers that could improve the staging, choice of therapy and management of OSCC. The identification of new biomarkers is awaited for better personalization of the surgical treatment of OSCC