Objective
Most cancer therapies target cell-intrinsic alterations or aim to boost immune-mediated cytotoxicity. Despite vast efforts, these strategies have not prevented or cured metastatic colorectal cancer (mCRC). A novel approach is needed. We propose to exploit a therapeutic target space revealed from the analysis of transcriptional plasticity. We will identify therapeutic drugs that treat plasticity not as a liability but as a tool to induce susceptibility. Objective 1 aims to develop a new classification of CRC based on intratumor heterogeneity (ITH): by single-cell and spatial transcriptomics, we will define common transcriptional programs and build a catalog of tumor cell state archetypes. We will then link ITH subtypes with clinical outcomes. Objective 2 searches for drugs (~2,400, mostly FDA-approved) that control plasticity: a pooled single-cell screen in PDOs representing the main ITH CRC subtypes will quantify drug-induced state shifts and nominate agents that constrain heterogeneity, generating second-hit–vulnerable states. Objective 3 will evaluate rational treatment combinations that would first reprogram composition through targeted manipulation of plasticity and then eradicate the induced vulnerable state. We will test efficacy of these novel strategies in minimal-residual-disease and overt liver metastasis preclinical CRC models. In Objective 4 we will exploit the phenotypic atlas of drug-induced reprogramming to validate mechanistic hypotheses using genetic approaches, defining key regulators of transcriptional plasticity. Together, we will establish a precision-oncology paradigm centered on targeting plasticity for mCRC. We expect to deliver at least one proof of principle therapeutic strategy tailored to each ITH CRC subtype, exploiting rational drug sequences that leverage plasticity as a vulnerability. Because our screening library emphasizes repurposable drugs, prioritized combinations will be well positioned for medium term clinical evaluation.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2025-ADG
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08028 Barcelona
Spain
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