Biology subjects

Foster, J. G.

Publications and source records attributed to Foster, J. G..

3 recordsLinked to original sources

bioRxiv2026

Transcriptome profiling of cell-free RNAs in prostate cancer patients on active surveillance

Active surveillance (AS) delays or avoids unnecessary treatment-related side effects for early localised non-aggressive prostate cancer (PCa) through monitoring with regular prostate-specific antigen (PSA) testing, digital rectal examination (DRE), magnetic resonance imaging (MRI) and prostate biopsy. Whilst baseline MRI has prognostic value and is increasingly used for disease monitoring, molecular biomarkers could be an adjunct to refine risk stratification and disease prognostication [2]. Unlike tissue-based genomic classifiers such as Decipher (Veracyte) and Prolaris CCP (Myriad), blood-based molecular testing for example cell-free RNA (cfRNA) offers minimally invasive real-time monitoring. Moreover, cfRNA may yield genetic information shed from different cell populations within the tumour microenvironment, as well as the host circulation, expanding the opportunities for biomarker discovery. Here, we test the feasibility of whole transcriptome profiling of cfRNAs from the blood of PCa patients under AS, exploring differences between patients with stable disease (SD), and progression to radical prostatectomy (RP).

cancer biology↗

bioRxiv2022

HNRNPA2B1 controls an unfolded protein response-related prognostic gene signature in prostate cancer

HNRNPA2B1 is associated with prostate cancer (PC) disease aggressiveness and underlies pro-tumourigenic cellular stress responses. By analysing >500 PC transcriptomes, we reveal that HNRNPA2B1 over-expression is associated with poor patient prognosis and stress response pathways. These include the "protein processing in the endoplasmic reticulum" (ER) pathway, which incorporates the unfolded protein response (UPR). By RNA-sequencing of HNRNPA2B1-depleted cells PC cells, we identified HNRNPA2B1-mediated down-regulation of UPR genes including the master ER-stress sensor IRE1, which induces ER proteostasis. Consistent with IRE1 down-regulation in HNRNPA2B1-depleted cells, we observed reduced splicing of the IRE1-target and key UPR effector XBP1s. Furthermore, HNRNPA2B1 depletion up-regulates expression of the IRE1-dependent decay (RIDD) target gene BLOC1S1, which is degraded by activated IRE1. We identify a HNRNPA2B1-IRE1-XBP1-controlled four gene prognostic biomarker signature (HIX) which classifies a subgroup of primary PC patients at high risk of disease relapse. Pharmacological targeting of IRE1 attenuated HNRNAPA2-driven PC cell growth. Taken together, our data reveal a putative novel mechanism of UPR activation in PC by HNRNPA2B1, which may promote an IRE1-dependent yet potentially-targetable recurrent disease phenotype.

cancer biology↗

bioRxiv2018

Dysregulation of splicing-related proteins in prostate cancer is controlled by FOXA1

Prostate cancer (PCa) is genomically driven by dysregulation of transcriptional networks involving the transcriptional factors (TFs) FOXA1, ERG, AR, and HOXB13. However, the role of these specific TFs in the regulation of alternative pre-mRNA splicing (AS), which is a proven therapeutic vulnerability for cancers driven by the TF MYC, is not described. Using transcriptomic datasets from PCa patients, we tested for an association between expression of FOXA1, ERG, AR, HOXB13, and MYC, and genes involved in AS - termed splicing-related proteins (SRPs), which have pleiotropic roles in RNA metabolism. We identified FOXA1 as the strongest predictor of dysregulated SRP gene expression, which was associated with PCa disease relapse after treatment. Subsequently, we selected a subset of FOXA1-binding and actively-transcribed SRP genes that phenocopy the FOXA1 dependency of PCa cells, and confirmed in vitro via knockdown and over-expression that FOXA1 regulates SRP gene expression. Finally, we demonstrated the persistence of a FOXA1-SRP gene association in treatment-relapsed castration-resistant PCa (CRPCa) patients. Our data demonstrate, for the first time, that FOXA1 controls dysregulated SRP gene expression, which is associated with poor PCa patient outcomes. Analogous to MYC-driven cancers, our findings implicate the therapeutic targeting of SRPs and AS in FOXA1-overexpressing PCa.

cancer biology↗