Origin of genomic instability: Understanding the biological influence of inflammation in the initiation of pancreatic tumorigenesis

Project Information

Onco-inflammation

Grant agreement ID: 101026137

DOI

10.3030/101026137

Project terminated on 31 August 2023

EC signature date 23 April 2021

Start date 1 September 2022

End date 31 August 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 172 932,48

EU contribution

€ 172 932,48

Coordinated by

FUNDACION PUBLICA ANDALUZA PROGRESO Y SALUD M.P.
Spain

Periodic Reporting for period 1 - Onco-inflammation (Origin of genomic instability: Understanding the biological influence of inflammation in the initiation of pancreatic tumorigenesis)

Reporting period: 2022-09-01 to 2024-08-31

Summary of the context and overall objectives of the project

Inflammation is suspected to be the first step leading to cancer due to alcohol consumption, tobacco smoking or air pollution between others. Little is known of how inflammation triggers genetic changes leading to tumorigenesis. In previous work I show that TGFb, a cytokine present during inflammation, is able to generate aneuploidy, polyploidy and plausible chromosomal rearrangements in breast cells. Such effects were mediated through the induction of the epigenetic reprogramming EMT, highlighting the effect of cellular plasticity in the generation of genomic variability. Then, in view to understand how inflammatory signaling can affect the genome integrity in vivo, I design the project Onco-Inflammation, to study one of the most lethal cancer, the pancreatic ductal adenocarcinoma (PDAC), where therapeutic options are greatly limited. Using several mice models of pancreatitis, we follow the establishment of genomic insults, and in particular focusing on the role of the epigenetic re-programming Acinar-Ductal-Metaplasia as well as the oncogene KRAS, primordial for tissue regeneration through cellular plasticity. We want to focus in particular in events such as whole genome doubling, nuclear envelope disruption and micronuclei.
By understanding the mechanisms behind the initiation of tumorigenesis, new therapeutic targets and early detection markers can be discovered, which are really needed to improve the diagnostic and prognostic of those patients.
The overall objective of this grant is to understand better the link better cellular plasticity, inflammation and genomic changes in an attempt to find new cures. During this grant, we develop this initial hypothesis into deeper biological understanding of the inflammation and cell plasticity’s roles on genomic instability. A parallel goal of the MSCA Individual Fellowship is to foster the development of the individual researcher. The results from this grant represent a crucial support to transition into an independent academic career.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

This grant initially planned for 2 years was divided in 5 work packages (WP). As the follow terminated earlier the grant at the end of the first year to accept another grant to transition into a PI position, she was able to perform part of WP1, WP4 and WP5.
During the period of the MSCA grant, we generated several mice models and tested the use of high-resolution imaging to detect genomic instability as described in the WP 1 as well as the use of IHC. Importantly, we confirm the validity of our hypothesis and generate promising preliminary data. To date, this project yields 1 review paper on genomic instability and 1 scientific manuscript in preparation.
We also started a collaboration with a chemistry laboratory to validate the use of nanoparticle controlled drug delivery. This work result in a publication in ACS Applied Materials & Interfaces.
The fellow also attended two conferences in the cancer field (WP5). The EACR European association for cancer research annual meeting at Torino in Italy as well as a Spanish conference in cancer ASEICA (Spanish association of cancer researchers) annual meeting. Those meetings have allowed to connect the fellow with several experts of her field and will lead to future collaborations within her new laboratory.
In term of divulgation (WP5), the follow participated in three major events to celebrate i)- the European night of researcher (Caixaforum) and ii)- 2 events for the women in science´s day (one with CONOCELAS program organized by the Spanish association of cancer researchers and one at local school).
Most importantly, the fellow applies to several grants and secure her stabilization and transition to a PI position. She started her laboratory in September 2023 at the University of Seville. She won the regional grant EMERGIA (as PI and 160.000 for lab expenses) as well a national grant from Agencia Estatal de Investigación (AEI) (as PI and 185.000 euros) ensuring her stabilization within the Spanish system.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This project was shortened due to the transition of the fellow to a PI position. Then, the preliminary results obtained during this grant will lead to a future publication as the fellow will continue this line of research in her laboratory.
- Progress beyond the state of the art
Using several innovative techniques such as high-resolution imaging, we observed and validated our hypothesis on the origin of genomic instability under inflammation. The results from this grant support our innovative idea and new concept about genomic instability and will open a new avenue and line of research in the cancer field.
- Expected results:
Results obtained during this grant confirmed the hypothesis of work and showed promising possibility in discovering new markers and therapeutic targets against genomic unstable cells in pancreas. Understanding better the origin of genomic instability is primordial in view to discover new therapeutics to fight initiation and progression of tumorigenesis. The long-term results of this grant will benefice all the society, as cancer research is one of the priority field of research.
- Potential impact:
Pancreatic cancer remains one of the cancers with the poorest prognosis, with an overall 5-year survival rate of about 5%, without much difference between high/middle/low-income countries. Discovery of new PDAC classification and treatment can greatly improve patient´s survival and wellbeing, and be beneficial for all society.
Furthermore, discoveries obtained in this type of cancer could be translated to other ones, having a broader impact in the society.

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