Journal Of Investigative Dermatology

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Updated: 2 hours 36 min ago

457 Cancer associated fibroblast profiling reveals endothelin signalling as a novel mediator of niche to tumour cross-talk in Basal Cell Carcinoma

Sun, 2019-09-01 00:00
Basal Cell Carcinoma (BCC) is known to rely heavily on its underlying mesenchyme but little is understood regarding how the various cell types interact. Histological and gene expression changes in the dermis surrounding the tumour have been reported in BCCs as compared to normal skin. Targeting the tumour-stroma interactions may therefore be a viable strategy in controlling BCC onset. We here performed RNA sequencing on sorted CD26+ BCC associated fibroblasts (BAFs) in the BCC niche to examine their impact on tumour development.

456 Bortezomib induces immunogenic cell death in melanoma and enhances immune responses in vivo

Sun, 2019-09-01 00:00
Apoptotic tumour cells express neo-antigens that are sensed by the immune system and drive effective antitumour responses. This ‘immunogenic cell death’ (ICD) can be elicited in vivo following bortezomib (26S proteasome inhibitor) treatment in some cancers. Here, we test whether bortezomib-induced ER stress and apoptosis in melanoma promotes ICD. We demonstrate that sub-clinical doses of bortezomib induced apoptosis in vitro. Classic hallmarks of ICD, including cell-surface expression of calreticulin, HSP70 and HSP90 and the secretion of HMGB1 and ATP by apoptotic melanoma cells, were detected following bortezomib treatment in human and murine melanoma cells, suggesting ICD initiation.

455 The Function of RIPK4 in Keratinocyte Proliferation and Tumorigenesis

Sun, 2019-09-01 00:00
Non-melanoma skin cancer (NMSC) represents the most common cancer in the United States with more than 3.5 million cases per year. Moreover, the incidence has increased significantly over the past 50 years, by as much as 200%. Squamous cell carcinoma (SCC) of the skin, a sub-type of NMSC, shows a greater potential for invasion and metastasis compared to other NMSC. A more thorough understanding of the pathogenesis of SCC could allow for better stratification of patients for risk of invasive, aggressive disease as well as establish new avenues for potential medical therapeutics targeting SCC pathways.

454 Occurrence of TRKAIII splice variant in melanoma: a pilot study

Sun, 2019-09-01 00:00
TrkA is a member of the transmembrane neurotrophin receptor family with a critical role in cell proliferation, survival and differentiation. TrkA oncogenic activation is an emerging driver in a wide variety of solid tumors, and TrkA-targeted therapies using inhibitors have been reported to exhibit marked and durable efficacy. An alternative TrkA splice variant, the TrkAIII, characterized by exon 6-7 skipping, exhibits spontaneous aberrant activation. We aimed to explore a potential oncogenic role for TrkA in cutaneous melanoma.

453 Endovascular progenitors initiate and drive de novo vascularisation in melanoma

Sun, 2019-09-01 00:00
The development of new vascular structures is a pre-requisite for melanoma growth and spread. We aimed to better identify and characterize the source of de novo endothelium in melanoma. Among Lin-CD34+ cells, expression levels of VEGFR2 and CD31 defined three distinct endothelial sub-populations. Lineage tracing of endothelial cells (Cdh5CreER/RosaYFP) demonstrated a maturation sequence from endovascular progenitor (EVP) via transit amplifying (TA) to fully differentiated (D) cells in B16 and HCmel12 melanoma.

452 Neural networks detect cutaneous basal cell carcinomas in histological sections

Sun, 2019-09-01 00:00
Basal cell carcinomas (BCCs) represent the most common malignancy in humans. Due to their high numbers, pathologists have limited time for the judgement of histologic sections of this tumor entity. Digital pathology is a tool to improve and simplify histologic diagnoses in terms of safety, quality and efficiency. The next step in digital pathology will be to further improve these features by providing diagnosis suggestions to the pathologists. This can be achieved using machine learning methods, also called artificial intelligence.

451 Meiomitosis, a novel mechanism of carcinogenesis in head and neck squamous cell carcinomas

Sun, 2019-09-01 00:00
Genomic instability results from a failure of efficient and accurate DNA replication during cell division or DNA repair. Our research focuses on the aberrant expression of select meiosis specific cancer/testis (meiCT) genes that have the potential to stimulate meiomitosis: the collision of both the meiotic and mitotic pathways in a neoplastic cell resulting in genomic instability. The mechanisms contributing to genomic instability in cancer are synonymous to processes that occur in prophase I of meiosis, that include homologous chromosome pairing, double strand break formation, synapsis and homologous recombination.

450 Sun exposed individual normal keratinocytes tolerate multiple cancer-causing mutations in vivo

Sun, 2019-09-01 00:00
The burden of somatic mutation in sun-exposed normal skin has been described to be as high as visceral carcinomas using bulk DNA sequencing approaches. Mutations in so called keratinocyte carcinoma “driver genes”, such as TP53 and NOTCH1, are also frequently detected. Here we use a single colony sequencing approach to determine the mutation profiles of individual normal keratinocytes isolated from the periphery of multiple separate patient squamous cell carcinomas (SCC). We find the burden of mutation in individual normal sun-exposed keratinocytes ranges orders of magnitude, from 0.3 single nucleotide variants (SNV) per mega-base (Mb) of exome-captured DNA to 30.9 SNV / Mb, similar to those reported in keratinocyte carcinomas (ranging 1 to over 100 SNV / Mb).

449 Deletion of fibroblast MMP-14 in the skin leads to reduced melanoma growth

Sun, 2019-09-01 00:00
Imbalances in proteolytic activities are implicated in the pathogenesis of many skin diseases and the aim of this work was to address the importance of fibroblast-derived MMP-14 in these processes. To this end, we generated mice with inducible deletion of MMP-14 in the dermal fibroblasts (MMP-14Sf-/-). These mice exhibited increased accumulation of dermal collagen, thickness, and stiffness. In vitro, accumulation of collagen was the result of the loss of MMP-14Sf-/- proteolytic activity, but not increased synthesis.

448 A comprehensive analysis of coding and non coding transcriptomic changes in cutaneous squamous cell carcinoma

Sun, 2019-09-01 00:00
Cutaneous Squamous Cell Carcinoma (cSCC) is the most common and fastest-increasing cancer with metastatic potential. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are novel regulators of gene expression and little is known about their altered expression in cSCC. To elucidate cSCC associated coding and non-coding transcriptomic changes, we performed RNA-seq of 9 cSCCs and 7 healthy skin samples. Differential expression analysis was performed by edgeR. CircRNAs were identified using the find_circ and CIRCexplorer pipelines.

447 Complement component C1r upregulates the expression of matrix metalloproteinase-1, -13 and -10 and promotes invasion of cutaneous squamous carcinoma cells

Sun, 2019-09-01 00:00
Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and its incidence is increasing worldwide. Previous studies have demonstrated the role of complement system in cSCC progression. In this study we have investigated in detail the mechanistic role of serine protease C1r, a component of the C1 complex of the classical pathway of complement system. CRISPR/Cas9 technology was used to generate C1r negative cSCC cell clones. Knockout of C1r was confirmed by sequencing the PCR product obtained by amplification of genomic DNA and by Western blot analysis of the conditioned media of the cell clones.

446 Tumorigenesis mediated by extracellular vesicles through a Dsg2/miR-146a/IL-8 signaling axis

Sun, 2019-09-01 00:00
Exosomes are small extracellular vesicles (EVs) that serve as intercellular messengers carrying lipids, proteins, and genetic material that have been shown to play a significant role in many pathological conditions including cancer. We recently demonstrated that the desmosomal cadherin Dsg2, a stem cell marker upregulated in many cancers including SCCs, modulates EV biogenesis. Here, using SCC cell lines overexpressing GFP, Dsg2/GFP, or Dsg2CACS/GFP, a mutant form of Dsg2 unable to be palmitoylated, we demonstrate that cell surface presentation of the wild-type, but not mutant, Dsg2 enhanced EV release.

445 NQO1 suppresses the growth of cutaneous squamous cell carcinoma cells

Sun, 2019-09-01 00:00
Cutaneous squamous cell carcinoma (SCC) is an easily occurred cancer, which can worsen the quality of life considerably. It is known that external stimulus such as ultraviolet (UV) radiation induces cutaneous SCC via provoking oxidative stress. NAD(P)H dehydrogenase 1 (NQO1) is a ubiquitous flavoenzyme that functions as a guardian against oxidative stress. However, the effect of NQO1 on cutaneous SCC is not clearly elucidated. In this study, we investigated the effect of NQO1 on cutaneous SCC cells using the recombinant adenoviruses that can upregulate and/or downregulate NQO1 expression.

444 Integrative characterization of β-catenin activation in melanoma

Sun, 2019-09-01 00:00
The β-catenin signaling pathway plays a key role in several cellular functions and is commonly deregulated in cancer, including melanoma. Malignant melanoma is a highly aggressive skin tumor that, due to its tendency to metastasize, and despite the recent development of targeted and immune therapies, is still the deadliest form of skin cancer. Activation of β-catenin signaling has been observed in deep penetrating naevi and human melanomas mainly through CTNNB1 (the gene encoding for β-catenin) and APC mutations, and non-genetic mechanisms.

443 Mechanisms of Keratinocyte-Melanoma Cell Interaction

Sun, 2019-09-01 00:00
Malignant melanoma is the most aggressive form of human skin cancer and shows an increasing incidence. The transformation from a normal melanocyte to a melanoma cell is a stepwise process and the complex mechanisms during early stages of tumor development remain incompletely understood. Based on the increased tumor incidence in Epidermolysis bullosa simplex (EBS), we hypothesize that keratinocytes affect early melanoma development through direct interactions or via indirect mechanisms involving cell-cell contacts, cytoskeletal proteins and by secretion of growth factors.

442 CLEC12B a new gene implicated in melanoma

Sun, 2019-09-01 00:00
A transcriptomic analysis from vitiligo patient skins allowed us to discover that CLEC12B is selectively and strongly expressed by melanocytes. The objective of this study was to investigate the role of CLEC12B in melanoma. Expression of CLEC12B was assessed in melanoma cell lines, nevi and melanoma samples. Using a lentivirus construct we overexpressed (Ov) or downregulated (Sh) CLEC12B in melanoma cells lines to assess the effect of its modulation on proliferation and cell cycle. The signaling pathway involved was then studied.

441 Overlapping functions of PARP1 and p63 in cutaneous squamous cell carcinoma

Sun, 2019-09-01 00:00
Cutaneous SCC (cSCC) is the second most frequent type of human malignancy worldwide primarily caused by chronic long-term sun exposure. Somatic mutations in the tumor suppressor gene TP53 have been shown to occur frequently in aged sun-exposed skin and to favor clonal expansion. In contrast, p63, a p53 family member, is rarely mutated in cancer and rather is overexpressed and/or amplified in squamous cell carcinomas. Several studies have shown that p63 overexpression leads to higher proliferation rates and an increased ability to contrast differentiation, cellular senescence and apoptosis.

440 BRN2 is a Non-Canonical Melanoma Tumor-Suppressor

Sun, 2019-09-01 00:00
While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is less well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here we show that BRN2 haploinsufficiency is sufficient to promote melanoma initiation and metastasis formation, acting as a non-canonical tumor suppressor.

439 Melanoma cells export functional proteasomes by way of microvesiculation: a possible mechanism for generation of plasmatic proteasomes

Sun, 2019-09-01 00:00
Plasmatic proteasomes (p-proteasomes) are a reliable marker for metastatic dissemination in melanoma patients. Recent works have suggested that p-proteasome partially originated from tumour cell secretion via exosomes, which are also considered as a new biomarker for metastatic melanoma. Our objectives were to investigate the origin, mechanism of secretion and functionality of the melanoma p-proteasomes. We show by proteasome purification either from culture supernatant of melanoma cell lines (A-375, SK-MEL-28) or from plasma of melanoma patients, that the extracellular proteasome is released essentially as an assembled 20S core particle, contrarily to proteasome analyzed from cell lysate, which presents additional 26S capped proteasome.

438 Development and Validation of an 80-Gene UV Biomarker Panel for Stratification of Skin Cancer Risk

Sun, 2019-09-01 00:00
Squamous cell carcinomas (SCCs) and pre-malignant actinic keratoses (AKs) are thought to develop secondary to ultraviolet radiation (UV) damage. However, only ∼10% of AKs progress and become SCCs. We use RNA NanoString nCounter® analysis to validate a novel, 80-gene UV radiation-associated biomarker panel for stratification of skin cancer risk. Based on our previous study, we selected 80 of the 125 highly conserved UV-responsive genes to validate for clinical utility as a biomarker panel for detecting cancer-prone skin lesions.

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