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Re-wiring tumor immune-evasive plasticity with mRNA therapy

Objective

Tumor phenotypic heterogeneity and plasticity lead therapy resistance and metastasis, being a major therapeutic challenge in oncology. Hence, beyond genomic alterations, precision medicine requires a deeper understanding of “driver phenotype states”. My group investigates how this concept underlies the limited benefit of immunotherapies in breast cancer (BC). Thus, I propose PLASTWIRE to dissect the identity of distinct tumor immune-evasive phenotypes in BC, and to attack them leveraging specific mRNA therapy to block phenotypic heterogeneity and boost BC immunity. The DISCOVERY PHASE of this proposal will address unbiased identification of malignant stem cell immune-evasive (SCIE) phenotypes and transcription factors (TFs) that govern these cell states by using a whole-genome TF library screening using a novel dual-cell state reporter of stemness and immune-evasion. Understanding the landscape of TFs governing aggressive stem cell and immune evasive phenotypes in cancer will reveal new opportunities to rewire “driver phenotype states”. Functional validations in preclinical BC models, and spatial mapping of the SCIE and other phenotypes in human BC samples will determine their clinical relevance. The ultimate goal of this proposal is the THERAPEUTIC PHASE leveraging mRNA therapy to introduce the precise expression of identified TFs suppressors of SCIE phenotypes or “phenotype state drivers”, thus constraining their plasticity and actionizing vulnerability to immune attacks enhancing immune-based therapies. This is a lock-in & wipe-out therapeutic strategy that can resolve unmet clinical needs of BC overcoming overarching challenges associated to cell plasticity, phenotypic heterogeneity and immunotherapy resistance.

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Keywords

Programme(s)

Topic(s)

Funding Scheme

HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

(opens in new window) ERC-2025-ADG

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Host institution

FUNDACIO INSTITUT HOSPITAL DEL MAR D INVESTIGACIONS MEDIQUES
Net EU contribution
€ 2 533 207,00
Address
Doctor Aiguader 88
08003 Barcelona
Spain
Region
Este Cataluña Barcelona
Activity type
Research Organisations
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Total cost
No data

Beneficiaries (1)