Characterization of the reciprocal interaction between oncogenes/chromatin remodelers in tumorogenesis and metastasis in lung cancer

Project information

The principal investigator of the project “Characterization of the reciprocal interaction oncogene/chromatin remodelers in tumorogenesis and metastasis in lung cancer” is Dr. Fernando Lecanda Cordero, from the Adhesion and Metastasis research group.

KRAS is the most frequently mutated oncogene in the most lethal tumors such as lung, colorectal and pancreatic cancer. Despite recent advances in multimodal therapies, metastasis is the most frequent cause of death in these patients, whose curative options are limited. Intra- and inter-tumor variation in tumor progression and metastasis is not always explained by the different genetic mutations found in patients. This phenomenon is explained by the epigenome of each individual at a given time.

The cellular epigenomic landscape is very dynamic and is determined by the exquisite control of multiple regulatory proteins including chromatin remodelers (DNA methyl- and demethyltransferases, de- and acetylases (HDAC/HAT), transcriptional co-regulators and non-coding RNAs (ncRNAs). Dysregulation of these components by the microenvironment or by somatic mutations can lead to critical changes in tumor behavior.

Aberrant epigenetic changes that alter the normal state of chromatin constitute one of the hallmarks of cancer. This deregulated epigenetic landscape involves post-transcriptional modifications of chromatin inducing aberrant control of transcription, replication, DNA recombination and repair, involved in a wide variety of key cellular processes in tumorigenesis and metastasis. In contrast to the irreversibility of genetic events in cancer, epigenomic alterations are potentially reversible and several FDA-approved drugs benefit cancer patients.

The complexity of the concomitant cooperation between epigenetic and genetic programs may explain tumor progression and dissemination, and limits the efficacy of conventional therapies. However, a mechanistic approach that focuses on the joint interaction of both aspects has been neglected. This project is designed to fill that gap.

The overall goal of the project is to integrate epigenetic and genetic data using biological and clinical information with robust computational analyses derived from transcriptomics, epigenomics, as well as a range of in vitro and in vivo assays using an animal model generated by the Crispr methodology, which integrates KRAS as an oncogenic alteration together with the loss of the chromatin modifier SETD2 as an epigenetic event. The characterization of the SETD2-regulated interactome as well as the transcriptional program activated by KRAS in this context could be critical for the characterization of new target genes modulatable by specific drugs. Furthermore, knowledge of the entire KRAS and SETD2 crosstalk-regulated network could provide new insights into potential predictive biomarkers of disease. The validation in lung adenocarcinoma samples from patients, of the panel of genes/interactors found in the animal model, would give a great translational relevance to the project with a potential improvement of the treatment chosen for each of the patients based on the deregulated gene panel.

The grant for this project is 50% co-financed by the European Regional Development Fund through the 2014-2020 ERDF Operational Program of Navarra. European Union. European Regional Development Fund. A way of doing Europe.

• Convocation: Proyectos de Investigación en Ciencias de la Salud 2017. Gobierno de Navarra Dtpo. Salud
• Reference: 77/2017
• Duration: 3 años
• Start date: December 15, 2017
• End date: December 14, 2020
• Funder: Comisión Europea
• Grant: 64.842,75 €
• Nature of project: European