Projektbeschreibung
Erkenntnisse über Resterkrankungen von Darmkrebs
Die meisten Menschen mit Darmkrebs unterziehen sich als erste Behandlungsmaßnahme einer chirurgischen Resektion. Doch in beinahe 40 % der Fälle tritt ein Rückfall mit metastasierenden Erkrankungen auf. Diese haben eine schlechte Prognose. Forschende des EU-finanzierten Projekts residualCRC setzten sich das Ziel, neuartige Strategien zu entwickeln, welche die Resterkrankung angreifen. Zu diesem Zweck sollen Tumorzellen untersucht werden, die sich in anderen Organen angesiedelt haben. Die Forschenden werden zu diesem Zweck mutierte Mäuse und Organoide einsetzen, welche die herausstechenden Merkmale von menschlichem metastasierendem Darmkrebs abbilden. Darüber hinaus werden sie transkriptionelle Profile einzelner Zellen erstellen und den Einfluss von Treibermutationen und Immunantworten auf das Verhalten der angesiedelten Tumorzellen analysieren.
Ziel
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.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-ADG - Advanced GrantGastgebende Einrichtung
08028 Barcelona
Spanien