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CORDIS

MECHANISMS BEHIND RESIDUAL DISEASE IN COLORECTAL CANCER and MODELLING OF THERAPIES THAT PREVENT RELAPSE

Project description

Insight into colorectal cancer residual disease

Most patients with colorectal cancer (CRC) undergo surgical resection as a first line of treatment. However, nearly 40 % of the cases relapse with metastatic disease and have a poor prognosis. Scientists of the EU-funded residualCRC project aim to develop novel strategies that target residual disease by studying tumour cells that have disseminated to other organs. For this purpose, they will employ mutant mice and organoids that reproduce key features of human metastatic CRC. Moreover, they will perform single cell transcriptional profiling and analyse the influence of driver mutations and immune responses on disseminated tumour cell behaviour.

Objective

Disease relapse is a major complication in colorectal cancer (CRC). At the time of diagnosis, the majority of patients will present with locoregional disease that can be effectively resected by surgery. This intervention is sufficient to cure the primary disease in most cases. Yet, over the course of the following months or years, around 40% of the patients that underwent resection of the primary tumor with curative intention will relapse, generally in the form of metastatic disease. As these metastases eventually interfere with the function of vital organs such as the liver and lungs, patients that undergo relapse have poor prognosis. Recurrent cancer arises from clinically occult tumor cells that have disseminated to foreign organs (disseminated tumor cells or DTCs) before surgical removal of the primary CRC. Although the time window between surgery and relapse offers a good opportunity to prevent metastasis, current therapies are not effective at eliminating DTCs. Thus, there is an important unmet need to develop strategies to target residual disease. Advances in this area will benefit a large proportion of patients.

Despite its clinical relevance, the study of residual disease in CRC has been largely neglected and the principles that govern the behavior of DTCs remain unknown. The main reason for this important knowledge gap is that residual tumor cells are difficult to study in patients, as they remain clinically occult. We have recently generated a unique set of compound mutant mice and organoids that reproduce key features of human metastatic CRC. We propose to leverage these new models to study the biology of residual disease. We will characterize the features of DTCs using single cell transcriptional profiling, analyze the influence of driver mutations on DTC behavior, explore mechanisms of immune evasion during the latency phase, and model DTC latency in vivo and in vitro. Our ultimate goal is to design therapies that prevent disease relapse in CRC.

Host institution

FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Net EU contribution
€ 2 500 000,00
Address
CARRER BALDIRI REIXAC 10-12 PARC SCIENTIFIC DE BARCELONA
08028 Barcelona
Spain

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Region
Este Cataluña Barcelona
Activity type
Research Organisations
Links
Total cost
€ 2 500 000,00

Beneficiaries (1)