Biology subjects

Rodger, E. J.

Publications and source records attributed to Rodger, E. J..

3 recordsLinked to original sources

bioRxiv2026

Elevated Expression of MALAT1 Contributes to the Survival of Drug-Tolerant Persister Cells Following Targeted Therapy in Lung Adenocarcinoma

Lung adenocarcinomas frequently harbour actionable oncogenic mutations that are vulnerable to treatment with targeted therapies. While responses to targeted therapies are often initially dramatic, relapse is almost inevitable and prevents durable responses in advanced-stage patients. Relapse is, in part, caused by drug tolerant persister cells (DTPs) which are able to survive treatment by entering a reversible, dormant state. Although long non-coding RNAs (lncRNAs) regulate processes thought to allow DTPs to survive and become stably resistant, the potential roles of lncRNAs in DTPs are largely unknown. In this study, we sought to investigate the expression of lncRNAs in in vitro DTP models of lung adenocarcinoma. We found that the lncRNAs Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) were enriched in DTPs and that knocking down MALAT1 enhanced the effect of targeted therapies in both EGFR- and KRAS-mutant DTP models. To better understand pathways that MALAT1 might regulate in DTPs, bulk RNA-sequencing was performed and several pathways that may contribute to the actions of MALAT1 in DTPs were identified. Overall, our work describes a role for the lncRNA MALAT1 in DTPs in NSCLC and suggests that MALAT1 may be a novel target for the prevention of drug tolerance and subsequent resistance to targeted therapy in NSCLC.

cancer biology↗

bioRxiv2021

Transcriptional reprogramming and constitutive PD-L1 expression in melanoma are associated with dedifferentiation and activation of interferon and tumor necrosis factor signaling pathways

Melanoma is the most aggressive type of skin cancer, with increasing incidence worldwide. Advances in targeted therapy and immunotherapy have improved the survival of melanoma patients experiencing recurrent disease, but unfortunately treatment resistance frequently reduces patient survival. Resistance to targeted therapy is associated with transcriptomic changes, and has also been shown to be accompanied by increased expression of programmed death ligand 1 (PD-L1), a potent inhibitor of immune response. Intrinsic upregulation of PD-L1 is associated with genome-wide DNA hypomethylation and widespread alterations in gene expression in melanoma cell lines. However, an in-depth analysis of the transcriptomic landscape of melanoma cells with intrinsically upregulated PD-L1 expression is lacking. To determine the transcriptomic landscape of intrinsically upregulated PD-L1 expression in melanoma, we investigated transcriptomes in melanomas with constitutive versus inducible PD-L1 expression (referred to as PD-L1CON and PD-L1IND). RNA-Seq analysis was performed on seven PD-L1CON melanoma cell lines and ten melanoma cell lines with low inducible PD-L1IND expression. We observed that PD-L1CON melanoma cells had a reprogrammed transcriptome with a characteristic pattern of dedifferentiated gene expression, together with active interferon (IFN) and tumor necrosis factor (TNF) signalling pathways. Furthermore, we identified key transcription factors that were also differentially expressed in PD-L1CON versus PD-L1IND melanoma cell lines. Overall, our studies describe transcriptomic reprogramming of melanomas with PD-L1CON expression. Simple SummaryMelanoma, an aggressive form of skin cancer, is frequently associated with drug resistance in the advanced stages. For instance, frequently resistance is observed to sequential treatment of melanoma with targeted therapy and immunotherapy. In this research, the authors investigated whether potential transcriptional mechanisms and pathways associated with PD-L1 protein expression could underlie targeted therapy drug resistance in melanoma. The authors found a PD-L1 expression transcriptional pattern underlies resistance to targeted therapy in a subgroup of melanomas. These melanomas were markedly dedifferentiated, as compared to melanomas that were not drug resistant. Understanding changes in transcription and molecular pathways that lead to drug resistance could allow researchers to develop interventions to prevent drug resistance from occurring in melanoma, which could also be relevant to other cancer types.

cancer biology↗

bioRxiv2021

The mouse papillomavirus epigenetic signature is characterised by DNA hypermethylation after lesion regression

The {beta} genus of human papillomaviruses (HPVs) infect cutaneous epidermis. They contribute to the development of cutaneous squamous cell carcinoma (cSCC) in individuals with epidermodysplasia verruciformis, and increase susceptibility to UV-induced cSCC. This has been demonstrated in UV-exposed mice previously infected with mouse papillomavirus (MmuPV1). However, the mechanism by which {beta}-HPVs contribute to cSCC is unclear. We propose that viral infection leaves a DNA methylation signature following resolution of the active lesion that may contribute to increased susceptibility to UV-induced cSCC. To test this, we carried out Reduced Representation Bisulphite Sequencing on DNA from tail skin of mice with actively infected lesions, MmuPV1-infected then healed lesions (regressed infection), and mock-infected control mice. Genome-scale DNA methylation libraries were generated and analysed for differentially methylated regions throughout the genome, and for HPV sequences. We found that DNA of active lesions was not differentially methylated compared to matched control mice. In contrast, 834 differentially methylated fragments were identified in regressed lesions compared to mock-infected control skin. An analysis of MmuPV1 viral DNA demonstrated retention of viral DNA in some of the lesions that had regressed. Overall, the viral sequences identified showed over-representation of sequences from the E4 region. The DNA hypermethylation that we found in regressed MmuPV1 lesions may be a factor in the increased susceptibility of mice to UV-induced cSCC. AUTHOR SUMMARYPapillomavirus infections can be asymptomatic, can cause warts, and in some cases can lead to cancer. There is direct evidence for mouse papillomavirus infection resulting in increased susceptibility to UV-induced cutaneous squamous cell carcinoma in a mouse model. We propose that DNA methylation following viral infection may contribute to the increased susceptibility. We describe the DNA methylation landscape during an active infection with mouse papillomavirus and following regression of the lesion. We found that there were very few differentially methylated DNA fragments during active infection. In contrast, over 800 differentially methylated DNA fragments were identified following regression of the lesion. This is the first description of the genome-wide DNA methylation landscape for mouse papillomavirus, to our knowledge. The dramatic DNA hypermethylation that we observe following resolution of infection may contribute to a hit and run mechanism for the increased susceptibility to UV-induced cancer by papillomaviruses.

pathology↗