Biology subjects

Roth-Carter, Q. R.

Publications and source records attributed to Roth-Carter, Q. R..

4 recordsLinked to original sources

bioRxiv2023

Crosstalk in skin: Loss of desmoglein 1 in keratinocytes inhibits BRAFV600E-induced cellular senescence in human melanocytes

Melanoma arises from transformation of melanocytes in the basal layer of the epidermis where they are surrounded by keratinocytes, with which they interact through cell contact and paracrine communication. Considerable effort has been devoted to determining how the accumulation of oncogene and tumor suppressor gene mutations in melanocytes drive melanoma development. However, the extent to which alterations in keratinocytes that occur in the developing tumor niche serve as extrinsic drivers of melanoma initiation and progression is poorly understood. We recently identified the keratinocyte-specific cadherin, desmoglein 1 (Dsg1), as an important mediator of keratinocyte:melanoma cell crosstalk, demonstrating that its chronic loss, which can occur through melanoma cell-dependent paracrine signaling, promotes behaviors that mimic a malignant phenotype. Here we address the extent to which Dsg1 loss affects early steps in melanomagenesis. RNA-Seq analysis revealed that paracrine signals from Dsg1-deficient keratinocytes mediate a transcriptional switch from a differentiated to undifferentiated cell state in melanocytes expressing BRAFV600E, a driver mutation commonly present in both melanoma and benign nevi and reported to cause growth arrest and oncogene-induced senescence (OIS). Of [~]220 differentially expressed genes in BRAFV600E cells treated with Dsg1-deficient conditioned media (CM), the laminin superfamily member NTN4/Netrin-4, which inhibits senescence in endothelial cells, stood out. Indeed, while BRAFV600E melanocytes treated with Dsg1-deficient CM showed signs of senescence bypass as assessed by increased senescence-associated {beta}-galactosidase activity and decreased p16, knockdown of NTN4 reversed these effects. These results suggest that Dsg1 loss in keratinocytes provides an extrinsic signal to push melanocytes towards oncogenic transformation once an initial mutation has been introduced.

cell biology↗

bioRxiv2022

Transcriptional profiling of rare acantholytic disorders suggests common mechanisms of pathogenesis

BackgroundDarier, Hailey-Hailey, and Grovers diseases are rare non-autoimmune acantholytic skin diseases. While these diseases have different underlying causes, they share defects in cell-cell adhesion in the epidermis and desmosome organization. ObjectiveTo better understand the underlying mechanisms leading to disease in these conditions we performed RNA-seq on lesional skin samples from Darier, Hailey-Hailey, and Grovers disease patients. MethodsRNA-seq and bioinformatics analyses were performed on banked paraffin embedded diagnostic samples from each disease. For detailed Methods, please see the Methods section in this articles Online Repository at www.jacionline.org. ResultsThe transcriptomic profiles of Darier, Hailey-Hailey, and Grovers disease were found to share a remarkable overlap, which did not extend to other common inflammatory skin diseases, psoriasis and atopic dermatitis. Analysis of enriched pathways showed a shared upregulation in keratinocyte differentiation and Th17 inflammatory pathways, and a decrease in cell adhesion and actin organization pathways in Darier, Hailey-Hailey, and Grovers disease. Direct comparison to atopic dermatitis and psoriasis showed that the downregulation in actin organization pathways was a unique feature in Darier, Hailey-Hailey, and Grovers disease. Further, upstream regulator analysis suggests that a decrease in SRF/MRTF activity may be responsible for the downregulation of actin organization pathways. Staining for MRTFA in lesional skin samples showed a decrease in nuclear MRTFA in patient skin compared to normal skin. ConclusionThese findings highlight the significant level of similarity in the transcriptome of Darier, Hailey-Hailey, and Grovers disease, and identify decreases in actin organization pathways as a unique signature present in these conditions. Key MessagesO_LIDarier Disease, Hailey-Hailey Disease, and Grovers Disease share similar transcriptional profiles suggesting common mechanisms of pathogenesis. C_LIO_LISRF/MRTFA activity is reduced in Darier Disease, Hailey-Hailey Disease and Grovers disease, implicating actin organization in acantholysis. C_LI

genomics↗

bioRxiv2022

Keratinocyte desmosomal cadherin Desmoglein 1 as a mediator and target of paracrine signaling in the melanoma niche

Melanoma is an aggressive cancer typically arising from transformation of melanocytes residing in the basal layer of the epidermis, where they are in direct contact with surrounding keratinocytes. The role of keratinocytes in shaping the melanoma tumor microenvironment remains understudied. We previously showed that temporary loss of the keratinocyte-specific cadherin, Desmoglein 1 (Dsg1) controls paracrine signaling between normal melanocytes and keratinocytes to stimulate the protective tanning response. Here, we provide evidence that melanoma cells hijack this intercellular communication by secreting factors that keep Dsg1 expression low in surrounding keratinocytes, which in turn generate their own paracrine signals that enhance melanoma spread through CXCL1/CXCR2 signaling. Evidence suggests a model whereby paracrine signaling from melanoma cells increases levels of the transcriptional repressor Snai2 (Slug), and consequently decreases the Dsg1 transcriptional activator Grhl1 (Grainyhead like 1), a known promoter of epidermal differentiation and barrier function. Together, these data support the idea that paracrine crosstalk between melanoma cells and keratinocytes resulting in chronic keratinocyte Dsg1 reduction contributes to melanoma cell movement associated with tumor progression.

cancer biology↗

bioRxiv2020

Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor

Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1s importance in epidermal integrity is underscored by genetic, autoimmune and bacterial toxin-mediated disorders interfering with Dsg1 function. Dsg1 loss-of-function mutations in humans result not only in skin lesions, but also multiple allergies, and isolated patient keratinocytes exhibit increased pro-allergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown. To determine the systemic response to Dsg1 loss, we deleted the three tandem Dsg1 genes in mice using CRISPR/Cas9. Whole transcriptome analysis of E18.5 Dsg1-/- skin showed changes consistent with the observed aberrant differentiation and barrier impairment. Comparing epidermal transcriptomes from E18.5 Dsg1-deficient mice and humans with Dsg1 mutations revealed a shared psoriatic-like IL-17-skewed inflammatory signature and less so a pro-allergic IL-4/13 signature. Although the impaired intercellular adhesion observed in Dsg1-/- mice resembles that resulting from autoimmune anti-Dsg1 pemphigus foliaceus antibodies, transcriptomic analysis of pemphigus skin lesions lacks a prominent IL-17 signature. Thus, beyond impairing the physical barrier, chronic loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth, possibly predisposing to skin inflammation.

immunology↗