Biology subjects

Somerville, T.

Publications and source records attributed to Somerville, T..

3 recordsLinked to original sources

bioRxiv2019

ZBED2 is an antagonist of Interferon Regulatory Factor 1 and modulates cell identity in pancreatic cancer

Lineage plasticity is a prominent feature of pancreatic ductal adenocarcinoma (PDA) cells, which can occur via deregulation of lineage-specifying transcription factors. Here, we show that the zinc finger protein ZBED2 is aberrantly expressed in PDA and alters tumor cell identity in this disease. Unexpectedly, our epigenomic experiments reveal that ZBED2 is a sequence-specific transcriptional repressor of interferon-stimulated genes, which occurs through antagonism of Interferon Regulatory Factor 1 (IRF1)-mediated transcriptional activation at co-occupied promoter elements. Consequently, ZBED2 attenuates the transcriptional output and growth arrest phenotypes downstream of interferon signaling in multiple PDA cell line models. We also found that ZBED2 is preferentially expressed in the squamous molecular subtype of human PDA, in association with inferior patient survival outcomes. Consistent with this observation, we show that ZBED2 can repress the pancreatic progenitor transcriptional program, enhance motility, and promote invasion in PDA cells. Collectively, our findings suggest that high ZBED2 expression is acquired during PDA progression to suppress the interferon response pathway and to promote lineage plasticity in this disease. SIGNIFICANCE STATEMENTPancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, attributed in part to lineage infidelity downstream of deregulated lineage-specifying transcription factors (TFs). Here we define the biological effects of a poorly understood TF ZBED2 in the most aggressive subtype of PDA, defined by the expression of squamous lineage markers. Our study reveals two molecular functions of ZBED2 in PDA cells: an inhibitor of interferon response genes and a modifier of epithelial lineage programs. Both functions can be explained by the ability of ZBED2 to antagonize the functional output of Interferon Regulatory Factor-1 (IRF1). Our study reinforces the concept of aberrant lineage identity in cancer and highlights an unexpected connection between interferon response pathways and squamous-subtype PDA.

cancer biology↗

bioRxiv2019

Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. While the tumorigenic consequences of this aberrant cell fate transition are poorly understood, recent studies have identified a role for the master regulator TP63 in this process. Here, we investigated whether squamous trans-differentiation of pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous-subtype pancreatic cancer cells secrete factors that convert quiescent pancreatic stellate cells into a specialized subtype of cancer-associated fibroblasts (CAFs) that express inflammatory genes at high levels. We use gain- and loss-of-function approaches in vivo to show that squamous-subtype pancreatic tumor models become enriched with inflammatory CAFs and neutrophils in a TP63-dependent manner. These non cell-autonomous effects occur, at least in part, through TP63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A as a key target. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.

cancer biology↗

bioRxiv2018

Use of a corneal impression membrane for the detection of Herpes Simplex Virus type-1

PurposeTo investigate the use of a corneal impression membrane (CIM) for the detection of Herpes Simplex Virus type 1 (HSV-1) in suspected Herpes Simplex Keratitis (HSK).\n\nMaterials and MethodsIn the laboratory study, swabs and CIMs made from polytetrafluoroethylene were spiked with different concentrations of HSV-1. DNA was extracted and real time PCR undertaken using 2 sets of primers. In the clinical study consecutive patients presenting with suspected HSK were included. For each patient, samples were collected from corneal lesions with a swab and a CIM in random order. Clinical details were collected using a standardised clinical form and patients were categorized into probable, presumed and possible HSK.\n\nResultsThere was no difference in the performance of both primer sets for all HSV-1 dilutions (p=0.83) or between a CIM and a swab (p=0.18). 110 patients were included. Seventy-three patients (66.4%) had probable, 20 patients (18.2%) presumed, and 17 patients (15.5%) possible HSV-1 keratitis. The HSV-1 detection rate was significantly higher using a CIM (40/110, 36.4%) than a swab (28/110, 25.5%) (p=0.004). In the probable HSV keratitis group, the detection rate using a CIM was 43.8% compared to 27.4% for a swab (p=0.004). The Cp values obtained for the conjunctival swabs were higher than those obtained for the CIMs (p<0.001).\n\nConclusionsIn suspected HSK, a CIM is a useful alternative to a swab and more likely to detect the presence of HSV-1.

microbiology↗