Transcriptional Analysis Reveals Evidence of Chronically Impeded ECM Turnover and Epithelium-to-Mesenchyme Transition in Scar Tissue Giving Rise to Marjolin's Ulcer.
Marjolin's ulcer (MU) is an aggressive malignancy arising within chronic wounds. A major cause is unhealed burn injuries. This results in well-differentiated squamous cell carcinoma (SCC). This study aimed to elucidate transcriptional changes leading to malignancy by investigating differentially expressed genes in squamous cells present in a SCC compared with MU. MU tumor cells were isolated from histologically confirmed biopsy of SCC within an unhealed burn scar. Epithelial cells (ECs) adjacent to the tumor were co-isolated and a SCC cell line was commercially purchased. mRNA from all three samples was isolated and its expression was quantified using RNASeq. A threshold of log2fold change >2-fold in either direction was considered "differentially expressed." Gene expression analysis revealed distinct differences in gene expression in MU cells compared with EC (665 genes), EC and SCC (1673 genes). Enrichment analysis confirmed that pathways most affected included 1) elevation of genes associated with extracellular matrix organization/degradation, 2) activation of DNA damage, and 3) activation of cytokine signaling. Our analysis revealed two key insights about chronic wound microenvironment conducive to ulceration. First, in EC vs. MU comparison, downregulation of Collagen and Matrix metalloproteinase families suggests chronically impaired extracellular matrix turnover giving rise to a fibrotic microenvironment. Second, in SCC vs. MU comparison, dysregulation of cadherin-mediated cell-cell adhesions is suggestive of epithelial-to-mesenchymal transitions, similar to those during development. Acquisition of epithelial-to-mesenchymal transition may underlie the high metastatic rate in MU tumors. Taken together, this sheds light on mechanisms that underlie the divergent clinical features of these cutaneous cancers.
From the *Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, †Department of Surgery, ‡Division of Physical Medicine and Rehabilitation, Department of Clinical Neurosciences, Cumming School of Medicine, Calgary, Alberta, Canada; §Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada; ‖The Calgary Firefighters' Burn Treatment Centre, Alberta, Canada; and ¶Hotchkiss Brain Institute, University of Calgary, Alberta, Canada.
Sarthak
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Sinha
Samuel
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Su
Matthew
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Workentine
Natacha
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Agabalyan
Min
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Cheng
Vincent
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Gabriel
Jeff
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Biernaskie
D001707:Biopsy, Needle; D002056:Burns / Q000150:complications / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D002908:Chronic Disease; D002921:Cicatrix / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D012333:RNA, Messenger / Q000235:genetics*; D012016:Reference Values; D017423:Sequence Analysis, RNA; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D012883:Skin Ulcer / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D015533:Transcriptional Activation
D012333:RNA, Messenger