VISION Invited lecture - Genomic instability, microenvironment and telomere homeostasis in colorectal cancer

Recording and presentation of the invited lecture that took place online on 4 November 2021 - Pavel Vodička, MD, Ph.D. - Genomic instability, microenvironment and telomere homeostasis in colorectal cancer.

Pavel Vodicka^1,2,3, Sona Vodenkova¹, Michal Kroupa^1,3, Alena Opattova^1,2,3, Kristyna Tomasova^1,3, Ludmila Vodickova^1,2,3

¹ Institute of Experimental Medicine, Czech Acad. Sci., Videnska 1083, Prague 4, Czech Rep.

² Inst. Biology and Med. Genet., 1st Faculty of Medicine, Charles University, Albertov 6, Prague 2, Czech Rep.

³ Biomedical Center, Faculty of Medicine in Pilsen, Charles University Prague, Pilsen, 30100, Czech Rep.

Colorectal cancer (CRC) continues to be one of the leading malignancies and causes of tumour-related deaths worldwide. Both impaired DNA repair mechanisms and disrupted telomere length homeostasis represent potential culprits in CRC onset, its dissemination in the body and prognosis. Above parameters are becoming critical as prognostic markers, since CRC therapy is based on compounds interacting with DNA. DNA repair capacity in CRC patients have recently been studied in order to address prediction of therapy response. Due to the substantial interindividual variations in DNA repair capacities and relative telomere length, these markers may pose a possible contribution in individualized therapeutical regimen of CRC patients. Telomere attrition, responsible for replicative senescence in healthy cells, may become a hallmark of malignant transformation of the cell due to by-passing cell cycle checkpoints. Telomerase – a key enzyme keeping homeostasis of telomere - is almost ubiquitous in advanced solid cancers, including CRC, and its expression is fundamental to cell immortalization.
Here we present our data based on the investigation of base excision repair capacities and relative telomere length in tumor tissues and adjacent non-malignant mucosa of sporadic CRC patients. The relative gene expression of telomerases is monitored as well. Particular attention will be dedicated to the CRC phenotypes and clinicopathological characteristics. We also addressed telomere homeostasis in peripheral blood lymphocytes of CRC patients in several consecutive samplings (at diagnosis, immediately after treatment and in additional follow-up intervals), which could provide us the insight into the treatment response. This aspect is of particular relevance, since there is currently a persistent effort to develop therapeutics, which are telomerase-specific and gentle to non-malignant tissue. However, in practice, we are at the dawn of clinical trials. Additionally, emerging crosstalks between DNA repair and telomere length homeostasis may cast some lights on a dynamic of genomic instability, a fundamental hallmark (or cause) of cancer.

Acknowledgement: GACR 21-04607X, 19-10543S, AZV NV18/03/00199