Research projects - Prostate Cancer Biology Lab
ETS transcription factor ESE3/EHF as a regulator of prostate epithelial cell differentiation and stem cell properties
This project continue the effort of the Prostate Cancer Biology group toward a comprehensive understanding of the tumor suppressor role of ESE3/EHF transcription factor in prostate gland development and tumorigenesis. ESE3/EHF is a member of the sub-family of epithelial-specific ETS transcription factors, normally expressed in epithelial tissues. Our laboratory was the first to report the tumor suppressor role of this transcription factor in the prostate. We propose that this epithelial-restricted transcription factor is an important barrier to malignant transformation and tumor progression in the prostate. Our laboratory has recently established the first mouse model with a prostate-conditional knockout of ESE3/EHF. Furthermore, we have generated mouse models of combined ETS alterations by crossing ESE3/EHF knockout mice with other genetically engineered mice (e.g., ERG transgenic, PTEN knockout). We are currently integrating multiple genomic approaches to address the role of ESE3/EHF in the transcriptional and epigenetic reprogramming that defines prostate epithelial cell differentiation and sets the basis for malignant transformation. To this end, we are performing in cellular and mouse models, bulk and single-cell RNA-seq studies to determine ESE3/EHF dependent cell-specific gene network, ChIP-seq to map genomic distribution of ESE3/EHF and other transcription factors, along with ATAC-seq and Hi-C to define accessibility and functional organization of the genome. This project will provide important new insights with a high potential to impact on clinical management of prostate cancer patients.
(This project is currently founded by grant SNF2020-2023)
Novel epigenetic players in castration-resistant prostate cancer: functional and therapeutic impact
Resistance to androgen deprivation therapy (ADT) represents the main barrier to the cure of metastatic prostate cancer. Escape mechanisms include increased cell plasticity, acquisition of stem-like properties and neuroendocrine differentiation. Complex epigenetic and transcriptional changes are associated with the disease evolution and play critical roles in acquiring aggressive and treatment-resistance traits. Understanding the events involved in the clinical progression of PC towards the castration-resistant and neuroendocrine state is highly relevant.
We have identified methionine adenosyltransferase 2a (MAT2A) as a critical co-factor in advanced PC. MAT2A catalyzes the formation of S-adenosylmethionine (SAM), the universal methyl donor for the methylation of DNA, RNA and histones. We propose that MAT2A is a key player in the crosstalk between epigenetic and metabolic processes underpinning PC evolution. We hypothesized that enhanced MAT2A expression, by controlling SAM availability and SAM-dependent methylation reactions, promotes epigenetic and epitranscriptomic changes that contribute to CRCP progression. Accordingly, we intend to evaluate the mechanisms linking MAT2A to tumor progression and provide a roadmap for defining the potential of MAT2A-targeting strategies for treating prostate cancer. Collectively, these studies will lead to deep understanding of the role of MAT2A in PC and will provide support for the feasibility and efficacy of MAT2A-targeted strategies to reverse CRPC.
(This project is funded by KFS grant 2023-2026)
Epigenetic cross-talks in ERG fusion positive prostate cancers
Gene fusions involving the transcription factor ERG (TMPRSS2:ERG) are very frequent in prostate cancer. This gene fusion determines the overexpression of ERG driven by the promoter of the androgen-responsive TMPRSS2 gene. However, the mechanism by which ERG contributes to the tumorigenesis and drives the progression from primary to metastatic and hormone-refractory prostate cancers is still unclear. The group has recently reported a molecular event in ERG protein that enhances ERG transcriptional activity. Looking for proteins that potentially interact and cooperate with ERG, the group discovered that the master epigenetic effector, EZH2, binds and adds a methyl group to ERG at lysine 362, acting as a co-activator. The overall goal of this project is to understand the mechanisms involved in ERG oncogenic activation in prostate cancer and its role in epigenetic reprogramming. To this end, we are currently combining molecular, genomic and functional studies in cell cultures and animal models. Collectively, the of multiple approaches along with the availability of transgenic and knockout mice, human and mouse engineered cell lines will lead to a deep understanding of the biological mechanisms underlying ERG-dependent tumorigenesis.
Extracellular vesicles in the management of prostate cancer progression
We have reported that ETS transcription factors directly control a network of microRNAs and that unique microRNA profiles were associated with distinct ETS gene alterations. This analysis lead to discovery of a novel oncogenic axis involving loss of ESE3/EHF and elevation of miRNA-424 leading to non-canonical activation of STAT3 by altered protein turnover. Extracellular vesicles (EVs) are relevant means for transferring signals across cells and facilitate propagation of oncogenic stimuli promoting disease evolution and metastatic spread in cancer patients.Recently, we reported that miRNA-424 was secreted in small extracellular vesicles/exosomes by tumor cells and released in the extracellular environment. This finding suggested that ESE3/EHF loss and miR-424 could affect, through exosome release, normal and cancer cells in the immediate proximity and at distal sites. In support of the relevance of this observation, we found that miR-424 was released in plasma exosomes, particularly in patients with castration-resistant disease. This relevant finding has spurred further investigation of the role of exosomes and their cargo in disease progression. We are currently performing proteomic analysis of the exosomes in prostate cancer patients, including benign, primary, metastatic, and CRPC. Parallel studies are evaluating the cargo of exosomes derived from multiple prostate cancer models. These studies, relying on the combined use of human samples, cell lines and mouse models, will lead to a deeper understanding of the role of extracellular vesicles and their cargo in prostate cancer pathogenesis.
