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.
