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BackgroundRenal cell carcinoma (RCC) comprises five major molecular and histological subtypes. The Birt–Hogg–Dubé (BHD) syndrome is a hereditary human cancer syndrome that predisposes affected individuals to develop renal carcinoma of nearly all subtypes, in addition to benign fibrofolliculomas, and pulmonary and renal cysts. BHD is caused by loss-of-function mutations in the folliculin (FLCN) protein. The molecular function of FLCN is still largely unknown; opposite and conflicting evidence of the role of FLCN in mammalian target of rapamycin signalling/phosphorylated ribosomal protein S6 (p-S6) activation had recently been reported.Results and MethodsHere, the expression pattern of murine Flcn was described, and it was observed that homozygous disruption of Flcn results in embryonic lethality early during development. Importantly, heterozygous animals manifest early preneoplastic kidney lesions, devoid of Flcn expression, that progress towards malignancy, including cystopapillary adenomas. A bona fide tumour suppressor activity of FLCN was confirmed by nude mouse xenograft assays of two human RCC cell lines with either diminished or re-expressed FLCN. It was observed that loss of FLCN expression leads to context-dependent effects on S6 activation. Indeed, solid tumours and normal kidneys show decreased p-S6 upon diminished FLCN expression. Conversely, p-S6 is found to be elevated or absent in FLCN-negative renal cysts.ConclusionIn accordance with clinical data showing distinct renal malignancies arising in BHD patients, in this study FLCN is shown as a general tumour suppressor in the kidney.

Laser marking is an attractive technique allowing high-speed and high spatial resolution identification of materials, mechanical parts, tools or packaging modules for traceability, advertising, security or trademark protection reasons. The laser marking process, however, is very sensitive to the chemical composition, physical properties and texture of processed surfaces. Researchers have investigated the role of surface chemistry and morphology of nickel-plated copper lids in achieving high optical contrast marking with a Q-switch Nd:YAG laser. Profilometry, scanning electron microscopy and x-ray photoelectron spectroscopy measurements have been carried out to characterize investigated samples. The results indicate that a low-contrast marking results from a poor ability of the laser to nanostructure the thermally unstable Ni(OH)2-rich surface. The primary mechanism of high-quality marking is related to laser-induced smoothing of the surface, and not to the modification of the chemical composition of the irradiated material. Laser marking of such color-modified lids leads to drastically improved both resolution and contrast of the process.

Abstract Background The colonic stem cell niche is established by a gradient of WNT, R-spondin, BMP factors and their antagonists along the colonic epithelial vertical axis. Telocytes (TCFoxL1+) are mesenchymal cell forming a 3D hub underneath the epithelium, identified as an important source of niche factors. Specifically, they express non-canonical (nc) WNT factors and are the richest source of BMPs. Disruption of the BMPs gradient has been shown to be related to the development of several gastrointestinal diseases like Inflammatory Bowel Diseases (IBD). Such chronic inflammation drives the onset of Colitis-Associated Cancer (CAC) in about 60% of IBD patients. We previously showed that following a chronic inflammatory stress, 50% of the KO mouse for the BMP receptor 1a in colon telocytes (Bmpr1a△FoxL1+) presented malignant epithelial transformations. These cancer-like regions showed an aberrant epithelial b-catenin localization and an enlargement of the double positive α-SMA+/Vimentin+ mesenchymal population. Purpose: Loss of BMP signaling in TCFoxL1+ affects the mesenchymal-epithelial crosstalk and makes the colonic epithelium vulnerable to injuries, promoting/perpetuating inflammation fostering CAC onset. Method Following a DSS-based chronic inflammatory challenge in mutant and control mice, TCFoxL1+ ultrastructure was analyzed using transmission electron microscopy. Expression levels of members of the WNT-BMP axis (BMPs, WNTs and associated antagonists) were evaluated by qPCR in tumor-like areas and adjacent tissue. YAP cellular localization was evaluated by immunofluorescence in colon after chronic DSS challenge in Bmpr1a△FoxL1+ mice and controls. To differentiate cancer-associated fibroblasts (CAFs) subtypes, myCAF (myofibroblastic) and iCAF (inflammatory), in tumor-like region and adjacent tissue, we used co-staining against gp38, ICAM, Tagln and αSMA. Result(s) Following a chronic DSS-challenge, electron microscopy analysis demonstrated that TCFoxL1+ in the control mice exhibited a shortening and erosion in their telopodes (Tp). TCFoxL1+ in Bmpr1a△FoxL1+ mice tumor-like regions presented an expanded endoplasmic reticulum with fragmented and dilated Tp. A significant increase in BMP 4, 5 and 7 and in Wnt5 (nc) was detected in Bmpr1a△FoxL1+ mice compared to controls. Confocal analysis revealed a strong nuclear accumulation of YAP in cancer-like regions in mutant mice compared to controls. Finally, tumour-like regions presented an heterogeneous distribution of iCAF and myCAF compared to controls. Conclusion(s) These results exposed that the disruption of TCFoxL1+ associated BMP signaling disturbs the WNT-BMP gradient essential for the optimal maintenance of the SC niche and thus impacting epithelial regeneration when under stress. Thus, defective TCFoxL1+ assume a key role in the poor regeneration process of the epithelium which in the end promotes the development and progression of CAC. Please acknowledge all funding agencies by checking the applicable boxes below CIHR Disclosure of Interest None Declared

Abstract Background The extracellular matrix (ECM) is a complex assembly of proteins that provide mechanical and biochemical stimuli to the epithelial and mesenchymal cells of the GI mucosa. Deficiencies in ECM assembly, protein production or excessive accumulation can lead to multiples pathologies including fibrosis and cancer. FoxL1+-Telocytes (TCFoxL1+) are subepithelial cells that form a network underneath the epithelium, contributing to the microenvironment that supports epithelial and immune cell homeostasis. We have previously shown that BMPR1A signaling deletion in TCFoxL1+ influences the microenvironment via stromagenesis, immune infiltration and colonic dysplasia in mouse model of GI diseases. However, the precise molecular and mechanical events that contributes to the onset of this state have yet to be elucidated. Aims Characterize the modulations in ECM biodynamics induced by BmpR1a-deficient TC FoxL1+ ( BmpR1a△FoxL1+) in mouse colon submucosa. Methods Matrisomics was performed to determine the inventory of ECM proteins expressed solely in the GI stromal compartment following tissue deconstruction of control and BmpR1a△FoxL1+ mice colons. Histological and biochemical methods were used to further characterize the collagen network and matrisome-associated modulations. Fluorescence In Situ Hybridization (FISH) was performed to study the bacterial presence in the mucosa. Results The set of identified proteins shows an enrichment for proteins involved in collagen network regulation, wound repair homeostasis and immune regulation such as Col1a2, Col3a1, Col6a4 and Coll14a1, as well as SerpinH1, MFAP4, ANXA1 and S100A9. Collagen network is affected with increased deposition and reorganization of fiber alignment. Unfolded collagen content was also increased in dysplastic areas of BmpR1a△FoxL1+ mouse colon with a concomitant increase in the collagen-chaperone SerpinH1. Validations of other targets indicate that BmpR1a△FoxL1+ mice deals with some type of tissue micro-injury and inflammation that is unresolved, creating a unfavorable microenvironment for tissue homeostasis. Conclusions Taken together, these results suggest that Bmp-signaling deficient TCFoxL1+ significantly contribute to the collagen network biodynamics through increased collagen deposition, fiber alignment reorganization and regulation of the collagen triple-helix assembly. Other matrisome modulations suggest a state of unresolved wound healing due to tissue injury, that could be the etiology of GI pathology and lead to more severe conditions upon various environmental triggers. Funding Agencies CIHR

BackgroundThe mechanical information contained in the basement membrane (BM) is translated into intracellular signals via a process called mechanotransduction. The integrin-mediated cellular adhesions are found at the center of this outside-in mechanism connecting specific extracellular matrix (ECM) proteins with intracellular adaptors proteins that relay the signal via F-actin cytoskeleton turnover, Rho GTPase activity and eventually down to the nucleus. Dysregulation in any step of this tightly controlled process is a major contributor of disease development. Mesenchymal Foxl1+-telocytes (TCs) are known as a communication hub between stromal and epithelial cells from their proximity to the BM and from their potential roles in epithelial mechanical support and cell signaling. We have shown that BMPR1A signaling deletion in TCs (TCΔBmpr1a) induces stem cell niche defects, stromagenesis and colonic dysplasia in mouse model of GI diseases. Thus far, no study explored TCs relevance in microenvironment biomechanics and its subsequent impact in epithelial mechanotransduction.AimsUnderstand how TCΔBmpr1a can modulate mechanotransduction to induce early dysplastic changes in mouse colon.MethodsMatrisomics was performed to determine the inventory of ECM proteins expressed solely in the GI stromal compartment following tissue deconstruction of control and TCΔBmpr1a mice colons. Collagen fibers analysis, histological and biochemical methods were used to further characterize the matrix biodynamics. Proteomics of the associated epithelial compartment was also done to expose mechanosensors and signaling cascades affecting cell behaviour.ResultsMatrisomics indicate modulations in fiber assembly proteins (collagens (CL), Decorin, Biglycan), ECM remodelling enzymes (LOXL1, TGM2), growth factors (LTBP1, WNT2B) and cell adhesion mediators (Periostin). This is associated with a reorganization in CL fiber alignment, cellular delocalization of TGM2 and increased unfolded CL content. TCΔBmpr1a leads to shortcomings in matrix assembly, hence variations in the ECM architecture and a novel epithelial mechanotransduction potential. Deregulations in matrix-to-cell communication were shown by proteomic analysis of the epithelial-enriched compartment of colonic dysplastic areas, with modulations of mechanosensors such as focal adhesion components (integrins, paxillin), F-actin cytoskeleton (gelsolin, RhoA) and nuclear lamina (Prelamin A/C, nesprin).ConclusionsTaken together, these results suggest that TCΔBmpr1a can reprogram epithelial cells by impacting on matrix biodynamics and epithelial mechanotransduction. Modulation in this fine regulated sequence of communication from TCs to the epithelial nucleus via ECM could lead to the etiology of GI pathologies.Funding AgenciesCIHR

NOT PUBLISHED AT AUTHOR’S REQUEST Funding Agencies: CIHRScholarship Universite de Sherbrooke FMSS Abdenour-Nabid, MD

Abstract NOT PUBLISHED AT AUTHOR’S REQUEST Funding Agencies: CIHR

Abstract NOT PUBLISHED AT AUTHOR’S REQUEST Funding Agencies CIHR

Abstract NOT PUBLISHED AT AUTHOR’S REQUEST Funding Agencies: CIHR