Targeting metastatic-initiating cells and immune evasion

Metastatic initiation in distant organs requires stem cell-like tumor initiation phenotypes, also called metastatic stem cells or metastasis-initiating cells (MICs). These stem cell-like phenotypes can be associated to immune-evasive and immunosuppressive properties through different mechanisms. We have shown that cancer stem cells (CSCs) are inherently associated to low antigen-presentation machinery (APM), making these cell populations invisible to the immune system. We have designed an innovative and unique tool to identify stem cell immune-evasive (SCIE) phenotypes: an IFN Stimulated Response Element (ISRE)-reporter system that faithfully report the APM levels, crossed it with a SOX2/OCT4+ CSC reporter. Using this tool, we propose an unsupervised drug screening analysis with repurposing and receptor inhibitor libraries to identify molecules that can suppress metastatic SCIE phenotypes. Multiple metastatic cell line models will be tested to have a preliminary validation of the most efficient drugs suppressing SCIE. In future research projects, the identified drugs in this proposal will be further studied by transcriptomic computational analysis of clinical data, and used in preclinical experimental metastasis assays in combination with immunotherapy. The results from this research will have translational impact in the metastasis research, and in immunooncology providing new immune-based therapies with feasible application in the clinical practice.

Metastasis is the leading cause of mortality in breast cancer, with the spread of malignant cells to distant organs marking a point of clinical incurable disease and poor prognosis. The initiation of metastatic growth in secondary sites depends on a subpopulation of tumor cells with stem cell-like properties, commonly referred to as metastatic stem cells or metastasis-initiating cells (MICs). Importantly, MICs also exhibit intrinsic mechanisms of immune evasion, which contribute to their survival during dissemination and colonization of new tissues. Thanks to the Beugstiftung prize we have been able to improve and validate an engineered dual reported system to follow MIC-like tumor cell states related to stemness and immune-evasion. We have proved that the reporter is replicating similar cell states observed in clinical breast cancer samples from single cell RNA-seq data computational analysis. Our efforts have focused on refining our detection tool, optimizing the methodology for the screening readout, and initiating a scalable screening process that has already yielded promising preliminary findings. With the reporter tool in place, we developed a preliminary screening pipeline to assess the system’s responsiveness across breast cancer cell lines with distinct metastatic potential. This methodological and optimisation steps have demonstrated feasibility and sensitivity, laying the foundation for a larger-scale drug discovery approach. Using both drug repurposing libraries and targeted receptor inhibitor libraries, we aim to identify small molecules capable of suppressing MIC cell states. The screening is being conducted across multiple metastatic cell line models, ensuring relevance and generalizability of hits. Thanks to the Beug Foundation funding, we have catalyzed the opening of a promising new line of investigation with high traslational potential focused on identifying ready-to-use therapeutic drugs that target metastasis-initiating cells (MICs).

acelia@imim.es

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