The Contributions of Cancer-Testis and Developmental Genes to the Pathogenesis of Keratinocyte Carcinomas.

Keratinocyte carcinomas are among the most prevalent malignancies worldwide. Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) are the two cancers recognized as keratinocyte carcinomas. The standard of care for treating these cancers includes surgery and ablative therapies. However, in recent years, targeted therapies (e.g., cetuximab for cSCC and vismodegib/sonidegib for BCC) have been used to treat advanced disease as well as immunotherapy (e.g., cemiplimab). These treatments are expensive and have significant toxicities with objective response rates approaching ~50-65%. Hence, there is a need to dissect the molecular pathogenesis of these cancers to identify novel biomarkers and therapeutic targets to improve disease management. Several cancer-testis antigens (CTA) and developmental genes (including embryonic stem cell factors and fetal genes) are ectopically expressed in BCC and cSCC. When ectopically expressed in malignant tissues, functions of these genes may be recaptured to promote tumorigenesis. CTAs and developmental genes are emerging as important players in the pathogenesis of BCC and cSCC, positioning themselves as attractive candidate biomarkers and therapeutic targets requiring rigorous testing. Herein, we review the current research and offer perspectives on the contributions of CTAs and developmental genes to the pathogenesis of keratinocyte carcinomas.

Tools used to assay genomic instability in cancers and cancer meiomitosis.

Genomic instability is a defining characteristic of cancer and the analysis of DNA damage at the chromosome level is a crucial part of the study of carcinogenesis and genotoxicity. Chromosomal instability (CIN), the most common level of genomic instability in cancers, is defined as the rate of loss or gain of chromosomes through successive divisions. As such, DNA in cancer cells is highly unstable. However, the underlying mechanisms remain elusive. There is a debate as to whether instability succeeds transformation, or if it is a by-product of cancer, and therefore, studying potential molecular and cellular contributors of genomic instability is of high importance. Recent work has suggested an important role for ectopic expression of meiosis genes in driving genomic instability via a process called meiomitosis. Improving understanding of these mechanisms can contribute to the development of targeted therapies that exploit DNA damage and repair mechanisms. Here, we discuss a workflow of novel and established techniques used to assess chromosomal instability as well as the nature of genomic instability such as double strand breaks, micronuclei, and chromatin bridges. For each technique, we discuss their advantages and limitations in a lab setting. Lastly, we provide detailed protocols for the discussed techniques.

In silico analyses of the tumor microenvironment highlight tumoral inflammation, a Th2 cytokine shift and a mesenchymal stem cell-like phenotype in advanced in basal cell carcinomas.

Basal Cell Carcinoma (BCC) represents the most common form of all cancers. BCC is characteristically surrounded by a fibromyxoid stroma. Previous studies have suggested a shift towards a Th2 response, an increase in T regulatory lymphocytes and the presence of cancer-associated fibroblasts in the BCC tumor microenvironment. In this study, we aimed to further characterize the BCC tumor microenvironment in detail by analyzing BCC RNA-Sequencing data and correlating it with clinically-relevant features via in silico RNA deconvolution. Using immune cell type deconvolution by CIBERSORT, we have identified a brisk lymphocytic infiltration, and more abundant macrophages in BCC tumors compared to normal skin. Using cell type enrichment by xCell, we confirmed the observed immune infiltration in BCC tumors and compared them to normal skin. We observed a shift towards Th2 immunity in advanced and vismodegib-resistant tumors. Tumoral inflammation induced by macrophage activity was associated with advanced BCCs, while lymphocytic infiltration was most significant in non-advanced tumors, likely related to an adaptive anti-tumoral response. In advanced and vismodegib-resistant BCCs, mesenchymal stem cell-like properties were observed. Particularly in vismodegib-resistant BCCs, fibroblasts and adipocytes were found at high number, which ultimately may contribute to the decreased drug delivery to the tumor. In conclusion, this study has revealed notable BCC tumor microenvironment findings associated with important clinical features. Microenvironment-altering agents may be used locally for "routine" BCCs and systematically for advanced or resistant BCCs.