Melanoma, a highly heterogeneous tumor, is comprised of a functionally diverse spectrum of cell phenotypes and subpopulations, including stromal cells in the tumor microenvironment (TME). Melanoma has been shown to dynamically shift between different transcriptional states or phenotypes. This is referred to as phenotype switching in melanoma, and it involves switching between quiescent and proliferative cell cycle states, and dramatic shifts in invasiveness, as well as changes in signaling pathways in the melanoma cells, and immune cell composition in the TME. Melanoma cell plasticity is associated with altered gene expression in immune cells and cancer-associated fibroblasts, as well as changes in extracellular matrix, which drive the metastatic cascade and therapeutic resistance. Therefore, resistance to therapy in melanoma is not only dependent on genetic evolution, but it has also been suggested to be driven by gene expression changes and adaptive phenotypic cell plasticity. This review discusses recent findings in melanoma phenotype switching, immunotherapy resistance, and the balancing of the homeostatic TME between the different melanoma cell subpopulations. We also discuss future perspectives of the biology of neural crest-like state(s) in melanoma.

Cancer is the second leading cause of mortality and morbidity in the developed world. Cancer progression involves genetic and epigenetic alterations, accompanied by aggressive changes, such as increased immune evasion, onset of metastasis, and drug resistance. Similar to cancer, DNA hypomethylation, immune suppression, and invasive cell behaviours are also observed in the human placenta. Mechanisms that lead to the acquisition of invasive behaviour, immune evasion, and drug and immunotherapy resistance are presently under intense investigations to improve patient outcomes. Here, we review current knowledge regarding the similarities between immune suppression and epigenome regulation, including the expression of repetitive elements (REs), endogenous retroviruses (ERVs) and transposable elements (TEs) in cells of the placenta and in cancer, which are associated with changes in immune regulation and invasiveness. We explore whether immune suppression and epigenome regulation in placenta offers novel insights into immunotherapy resistance in cancer, and we also discuss the implications and the knowledge gaps relevant to these findings, which are rapidly being accrued in these quite disparate research fields. Finally, we discuss potential linkages between TE, ERV and RE activation and expression, regarding mechanisms of immune regulation in placenta and cancer. A greater understanding of the role of immune suppression and associated epigenome regulation in placenta could help to elucidate some comparable mechanisms operating in cancer, and identify potential new therapeutic targets for treating cancer.

Renal cell carcinoma (RCC) is the most common form of kidney cancer, consisting of multiple distinct subtypes. RCC has the highest mortality rate amongst the urogenital cancers, with kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and kidney chromophobe carcinoma (KICH) being the most common subtypes. The Paired-box (PAX) gene family encodes transcription factors, which orchestrate multiple processes in cell lineage determination during embryonic development and organogenesis. Several PAX genes have been shown to be expressed in RCC following its onset and progression. Here, we performed real-time quantitative polymerase chain reaction (RT-qPCR) analysis on a series of human RCC cell lines, revealing significant co-expression of PAX2, PAX6, and PAX8. Knockdown of PAX2 or PAX8 mRNA expression using RNA interference (RNAi) in the A498 RCC cell line resulted in inhibition of cell proliferation, which aligns with our previous research, although no reduction in cell proliferation was observed using a PAX2 small interfering RNA (siRNA). We downloaded publicly available RNA-sequencing data and clinical histories of RCC patients from The Cancer Genome Atlas (TCGA) database. Based on the expression levels of PAX2, PAX6, and PAX8, RCC patients were categorized into two PAX expression subtypes, PAXClusterA and PAXClusterB, exhibiting significant differences in clinical characteristics. We found that the PAXClusterA expression subgroup was associated with favorable clinical outcomes and better overall survival. These findings provide novel insights into the association between PAX gene expression levels and clinical outcomes in RCC patients, potentially contributing to improved treatment strategies for RCC.

Melanoma comprises <5% of cutaneous malignancies, yet it causes a significant proportion of skin cancer-related deaths worldwide. While new therapies for melanoma have been developed, not all patients respond well. Thus, further research is required to better predict patient outcomes. Using long-range nanopore sequencing, RT-qPCR, and RNA sequencing analyses, we examined the transcription of BARD1 splice isoforms in melanoma cell lines and patient tissue samples. Seventy-six BARD1 mRNA variants were identified in total, with several previously characterised isoforms (γ, φ, δ, ε, and η) contributing to a large proportion of the expressed transcripts. In addition, we identified four novel splice events, namely, Δ(E3_E9), ▼(i8), IVS10+131▼46, and IVS10▼176, occurring in various combinations in multiple transcripts. We found that short-read RNA-Seq analyses were limited in their ability to predict isoforms containing multiple non-contiguous splicing events, as compared to long-range nanopore sequencing. These studies suggest that further investigations into the functional significance of the identified BARD1 splice variants in melanoma are warranted.