In the fight against tumours, how the key driver mutations related to disease progression and metastatic spread regulate gene expression to promote ultimately tumor progression and cancer cell adaptation to therapies have remained largely elusive. Using the gene expression fingerprint of cancer cells, researchers at the Istitute of Oncology Research (IOR, affiliated to USI Università della Svizzera italiana) in Bellinzona have now developed a novel method to track precisely prostate cancer progression in an unprecedented manner. Nature Communications published these findings in early December.
Comprehensive genomic studies have delineated key driver mutations linked to disease progression and metastatic spread for most cancers. However, how these driver mutations regulate gene expression to promote ultimately tumor progression and cancer cell adaptation to therapies have remained largely elusive. Gene expression includes the formation of messenger RNA (mRNA) on a DNA template (transcription) and the synthesis of the corresponding protein (translation). Using the gene expression fingerprint of cancer cells, researchers at the Institute of Oncology Research (IOR, affiliated to USI Università della Svizzera italiana) in Bellinzona have now developed a novel method to track precisely prostate cancer progression in an unprecedented manner.
The scientists at the IOR generated a comprehensive gene expression atlas for prostate cancer by jointly reprocessing the raw data from 1200 prostate cancer patients raging from primary to end-stage disease. The atlas enabled the researchers to discover a uniform and predictable trajectory to disease progression, which involves the same transcriptional modification occurring overtime. In fact, the heterogenous mutational landscape of the disease only seems to determine the speed at which this process occurs. This is the discovery of the researchers of the Functional Cancer Genomics Group, led by Prof. Jean-Philippe Theurillat, MD. “Although the clinical course of prostate cancer is highly variable, having a detailed understanding of its roadmap to progression allows the development of new therapeutic interventions".
“This implies – explains the first author of the study Dr Marco Bolis, PhD - that we are able to anticipate which biological mechanisms are activated by the tumor cells to adapt to pharmacologic interventions that inhibit the androgen receptor – the key therapeutic target in this disease”. In this way, researchers can anticipate tumor progression and act pharmacologically when tumor adaptation has yet to occur.
“The gene expression atlas we have generated constitutes thus far the most comprehensive transcriptomic compendium (mRNA) of prostate cancer, ranging from normal prostate tissue to primary, and metastatic disease”, comments PhD candidate Arianna Vallerga, co-first author of the study.
“Additionally, in our study, we showed how early inhibition of the protein product of gene EZH2, which is among the major markers associated to the progression trajectory, reverts disease progression of prostate cancer cells and associated changes in the tumor microenvironment”, explains Dr. Daniela Bossi, Ph.D., co-first author of the study.
Having a clear understanding of disease progression will spark the development of therapeutic approaches aimed at preventing disease progression. In fact, co-targeting EZH2 with inhibition of androgen receptor signaling is already in early clinical development and the results look indeed encouraging. On the other hand, the ability to accurately quantify disease progression in clinical tissue samples and model organisms will also help apply findings from the laboratory into the correct clinical setting. In this perspective, the researchers have generated a web tool that enables the mining of the gene expression atlas in a highly personalized manner. The tool also enables the quantification of a prostate cancer progression from new samples. The long-term goal is to constantly extend the current web tool with new features, and thereby, build up an internationally recognized reference tool for the entire research community.
Dynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression is the title of the study conducted at the IOR. The full version is available online at >> www.nature.com/articles/s41467-021-26840-5