Juan Iovanna and colleagues report in Nature Communications on the essential role of epigenetics in the determinism of pancreatic cancer
Reporting in the journal Nature Communications, Dr. Juan Iovanna (Inserm) and colleagues at the Center for Cancer Research in Marseille (CRCM) and the Paoli-Calmettes Institute (IPC), in close collaboration with the project Map Tumor Identity Model (CIT) of the French National League against Cancer, the University of Wisconsin and the Mayo Clinic in the United States, describes a multi-factorial integrative, whole-genome-scale analysis of epigenetic modifications that characterize heterogeneity of pancreatic tumors. With less than 5% survival 5 years after diagnosis, pancreatic cancer has the poorest prognosis of all cancers. To date, surgery remains the best possible treatment for 15 to 20% of patients whose tumor is operable, with a life expectancy of 15 to 18 months: malignant metastases frequently appear after the operation. In the stage of metastatic development, the lifespan is then estimated between 3 and 6 months on average. Chemotherapy and radiotherapy are only marginally effective.
Like other cancers, pancreatic cancer results from the combination of genetic, epigenetic (biochemical modifications of the DNA) and environmental factors, which cause very heterogeneous profiles of the disease, with highly contrasting profiles of symptoms, predisposition to the formation of metastases, and especially responses to patient treatments. Because of this heterogeneity, it is essential to be able to stratify patients, ie to be able to distinguish different types of patients according to the aggressiveness profile of their tumors and their profile of responsiveness to available treatments. Labeled by the French National League against Cancer, Dr. Iovanna's Inserm team has generated a library of around 200 living human pancreatic tumors (PDAC), in the form of xenografts in mice and cells derived from these tumors. The analysis of these models reveals that they reproduce in a remarkable way the characteristics of the tumors in the patient, in particular the existence of 2 distinct subgroups with a very contrasting aggressiveness profile between the two groups.
The team then conducted a series of 'omics', that is to say, genome-wide, analysis of epigenetic modifications of the xenografted tumors in the mouse of DNA residues, such as the affixation of methyl residues on DNA (methylation of DNA) or on proteins that compact DNA (markings on histones), sites of occupation by factors regulating DNA sequences that control gene expression, and overall gene expression.
This extensive multi-omic profiling revealed that although genetic mutations are essential for the appearance of tumors, they do not condition the evolution of the disease. So, as the mutations are the same in all tumors, the question is to understand how are aggressiveness and response to treatments regulated?
The theoretical principle of this work is that two cells of the same organism, containing the same genetic material, can be extremely different, such as for example a brain cell and a skin cell. This variation is controlled by epigenetic mechanisms. If two cells containing the same genetic material can give rise to two different cell types, then the behavior of two pancreatic tumors, with the same genetic abnormalities, could be controlled by epigenetics. Epigenetics is the main mechanism of regulation of gene expression. The team then mapped all epigenetic signs at the full genome level and simultaneously measured the expression of all genes in a cohort of pancreatic tumors. An integrative and very thorough bioinformatic analysis has allowed to determine that the behavior of pancreatic tumors is indeed controlled at the level of the epigenome. In addition, the epigenetic characteristics observed are consistent with the changes in the expression of oncogenes known to be responsible for the development of pancreatic tumors; epigenetic modifications therefore contribute to the development and / or maintenance of the carcinogenic potential of tumors.
Finally, and most importantly, Juan Iovanna and his colleagues provide in their paper the proof of concept that a pharmacological treatment targeting epigenetic modifications can modify the characteristics of the most aggressive tumors so as to give them characteristics of less aggressive tumors, which are easier to management medically and have a better prognosis. One could also consider, and this could be revolutionary for this disease, that the opportunity to manipulate the pancreatic cancer epigenome could be exploited to transform a cancer-resistant tumor into a sensitive tumor and heal it.
In summary, the data presented in this work provide a comprehensive description of the epigenetic modifications responsible for the heterogeneity of pancreatic tumors, which allows an analysis of the pathological and molecular characteristics of the tumor, an analysis of the molecular mechanisms responsible for the progression of the disease, and a reliable prediction of their impact on the survival time of the patient. It describes epigenetic modifications in specific areas of the genome that can be used as biomarkers to refine the diagnosis, monitor patients during their treatment, or to identify the most appropriate treatment for the given patient. Finally, it allows the pharmacological treatment of pancreatic cancer with epi-drugs (drugs that affect epigenetic modifications), some of which are already in clinical trials and / or have already been authorized for other diseases.
DISTINCT EPIGENETIC LANDSCAPES UNDERLIE THE PATHOBIOLOGY OF PANCREATIC CANCER SUBTYPES
Gwen Lomberk, Yuna Blum, Rémy Nicolle, Asha Nair, Krutika Satish Gaonkar, Laetitia Marisa, Angela Mathison, Zhifu Sun, Huihuang Yan, Nabila Elarouci, Lucile Armenoult, Mira Ayadi, Tamas Ordog, Jeong-Heon Lee, Gavin Oliver, Eric Klee, Vincent Moutardier, Odile Gayet, Benjamin Bian, Pauline Duconseil, Marine Gilabert, Martin Bigonnet, Stephane Garcia, Olivier Turrini, Jean-Robert Delpero, Marc Giovannini, Philippe Grandval, Mohamed Gasmi, Veronique Secq, Aurélien De Reyniès, Nelson Dusetti, Juan Iovanna, Raul Urrutia