TT-EPIC · Deciphering Tolerogenic, Tumor-induced Epigenetic imprints in myeloid precursors

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Project objective

Despite successful surgical removal of primary tumors, many cancer patients ultimately succumb to metastatic relapse, often years after apparent cure. How tumors imprint long-lasting changes on the immune system that favor this deadly recurrence remains largely unknown. Tumors can epigenetically and transcriptionally reprogram bone marrow progenitors, establishing a “trained tolerance” state in myeloid cells that promotes immune evasion and metastasis. I hypothesize that tumor-derived factors induce long-lasting epigenetic and transcriptional reprogramming of bone marrow myeloid progenitors, establishing a state of Tumor-Trained Tolerance (TTT) that promotes systemic immune suppression and metastatic susceptibility even after complete removal of the primary tumor. Using melanoma as a clinically relevant model, I will dissect how tumor-induced reprogramming persists after tumor resection, identify the key molecular regulators, including MYC and epigenetic factors, and test whether these alterations can be reversed to restore immune vigilance. By integrating single-cell multi-omics (scRNA-seq, scATAC-seq, CITE-seq), proteomics, and targeted epigenetic profiling (histone marks and DNA methylation), I will map the regulatory networks underlying trained tolerance. Functional perturbations with CRISPR-based and pharmacological tools will determine causality and assess the potential to prevent metastasis. Finally, analysis of blood samples from melanoma patients will evaluate whether these signatures are conserved in humans, providing translational insight. This project combines cutting-edge molecular, computational, and in vivo approaches to reveal the hidden systemic consequences of primary tumors, aiming to uncover novel strategies to prevent the deadliest phase of cancer: metastatic relapse.

Original text from CORDIS.

Participants

• VIB VZW · ZWIJNAARDE - GENTCoordinatorBelgium

Links

• View on CORDIS
• DOI: 10.3030/101272730