Single Cell EPigenomic, Transcriptomic, and structural Rearrangement profiling to investigate Evolution in prostate cancer

Project Information

SCEPTRE

Grant agreement ID: 898956

DOI

10.3030/898956

Project closed

EC signature date 23 March 2020

Start date 10 April 2021

End date 9 April 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 174 806,40

EU contribution

€ 174 806,40

Coordinated by

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Germany

Periodic Reporting for period 1 - SCEPTRE (Single Cell EPigenomic, Transcriptomic, and structural Rearrangement profiling to investigate Evolution in prostate cancer)

Reporting period: 2021-04-10 to 2023-04-09

Summary of the context and overall objectives of the project

Prostate cancer is the most commonly diagnosed cancer in men in the European Union, with a significant global impact. However, treating Prostate cancer is challenging due to its diverse nature. Different types of Prostate cancer exhibit distinct molecular and clinical characteristics, making it crucial to target treatments effectively. While recent research has shed light on genetic and transcriptomic variations, the role of epigenetics (changes in gene activity), such as DNA methylation, remains understudied.

Understanding the epigenomic landscape of prostate cancer is vital for improving diagnosis and treatment outcomes. Current therapies may not be tailored to specific prostate cancer subtypes, leading to potential inefficacies and unnecessary side effects that not only affect patients' well-being but also incurs substantial healthcare costs.

The SCEPTRE project focused on interdisciplinary research at the interface between artificial intelligence; genomic analysis, and translational research in prostate cancer. The overall objectives were:

1. Uncover DNA methylation alterations in prostate cancer: To elucidate DNA methylation variations in prostate cancer, we have analyzed an extensive dataset of prostate cancer cases, aiming to discern epigenetic discrepancies between primary tumors and metastatic sites. We aimed to ascertain their impact on gene expression and their pivotal role in tumor progression.

2. Uncover rare and diverse cell populations in prostate cancer: Developed and implemented state-of-the-art computational methodologies for the comprehensive analysis of individual cells within prostate tumors. This has enabled the thorough examination of rare and diverse cellular subpopulations, offering valuable insights into the cancer's origins and evolutionary trajectories.

3. Identification of novel genetic and epigenetic drivers in prostate cancer: Leverage cutting-edge long-read sequencing methods to facilitate the precise detection of concurrent genetic and epigenetic alterations, providing a deeper understanding of their contributions to tumor evolution.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Over the course of the SCEPTRE project, we have made significant progress in understanding the epigenetic and genetic heterogeneity of prostate cancer. Here are the key achievements:

Blueprint of the epigenetic landscape in Prostate cancer
We have successfully derived a comprehensive blueprint of the DNA methylation (a specific epigenetic alteration) landscape of prostate cancer samples spanning less aggressive, very aggressive, and metastatic prostate cancer. We used a detailed approach to understand different layers of alterations in the DNA makeup of prostate tumors.

Tumor micro-environment: By examining molecular signatures from cells from the tumor and surrounding tissue (microenvironment), we could detect the amount of specific types of immune cells infiltrating prostate tumors. We discovered that higher abundance of certain immune subtypes was linked to worse cancer outcomes.

Markers of proliferation: We found two distinct patterns of DNA methylation changes related to how quickly the cancer cells multiply. These signatures were associated with higher aggressiveness as well as worse cancer outcomes.

Epigenetic drivers: We identified specific DNA regions that lose their normal methylation patterns and could potentially be the driver of the deregulation of key genes in prostate tumors. Understanding these changes have helped us understand how prostate cancer initiates and progresses, and could be leveraged to develop targeted therapies for prostate cancer.

Prostate cancer at cellular resolution

Researchers usually analyze DNA methylation profiles by averaging data from many sequences, giving an overall picture of methylation in all tumor cells. However, we took a unique approach, delving into the details at the single-read level. This allowed us to simulate a closer look, akin to studying individual cells. This method unveiled insights into cell development and identified distinct cell populations within tumors. Through this, we determined the rate of epigenetic changes and found specific regions with highly organized methylation loss, indicating a targeted process only within a subset of cells on the tumor. These alterations were associated with increased activity with key genes involved in cancer cell growth as well as deregulation of male hormones. This discovery sheds light on the intricate dynamics of methylation in prostate cancer, suggesting a vital role in its development.

Exploitation
We envisage a potential translation of these biomarkers in liquid biopsies (blood-based biopsies), that are a non-invasive method to detect and monitor the presence tumor-derived biomarkers in the bloodstream. This will be a critical next step in our pursuit of personalized medical care for prostate cancer.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The SCEPTRE project has made significant strides in advancing our understanding of prostate cancer through the integration of distinct molecular data (epigenomic, genomic, and transcriptomic data). Specifically, the project has successfully identified robust DNA methylation-based biomarkers across various regulatory layers, including the tumor microenvironment, markers of proliferation, and epigenetic regulation. This represents a substantial leap forward in our ability to comprehensively characterize prostate cancer at the molecular level. By leveraging DNA methylation as a powerful profiling method, this research has achieved a level of precision and depth that surpasses current standards.

Successful translation of this project can deliver novel diagnostic and therapeutic applications into the clinic and move us closer to precision medicine, an approach to cancer care that tailors medical treatment and interventions to the individual characteristics of each patient. We envisage a potential translation via liquid biopsies (blood-based biopsies) that has far-reaching socio-economic implications. This approach not only enhances patient comfort and safety through non-invasive procedures but also streamlines the diagnostic process, reducing healthcare costs associated with traditional tissue biopsies. Liquid biopsies also enable early detection and real-time monitoring capabilities that can significantly improve survival rates and enable more effective and personalized interventions. Overall, this would lead to a positive impact on both individual lives and the broader healthcare system.

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