{"doi":"10.1101/2025.05.03.652034","title":"Ischemic Injury Drives Tumor Growth via Accelerated Hematopoietic Aging","abstract":"Background: Patients with peripheral artery disease have increased risk of cancer development. Aging-associated changes in hematopoietic stem and progenitor cells (HSPCs), including inflammation and increased myelopoiesis, are implicated in both cardiovascular disease (CVD) and cancer, but their contributions to CVD-driven tumor progression are unclear. Objectives: To study cancer growth following peripheral ischemia and consequent changes within the HSPC bone marrow compartment to uncover mechanisms through which altered hematopoiesis promotes oncogenesis. Methods: Mammary cancer cell (E0771) growth was monitored in C57BL/6J mice after hind limb ischemia (HLI) or sham surgery. The tumor immune microenvironment, circulatory immune cells, and HSPC compartment were assessed by flow cytometry. Next-generation single-cell RNA and ATAC sequencing of HSPCs was performed to assess transcriptomic and epigenetic changes. The functional impact on tumor progression and persistence of ischemia-induced epigenetic reprogramming of HSPCs and their myeloid progeny was examined by bone marrow transplantation. Results: myeloid-biased hematopoietic stem cells (HSCs). This was associated with accelerated breast cancer growth and increased accumulation of tumoral immunosuppressive regulatory T cells and monocytes. Increased myelopoiesis was also supported by multiomic analyses showing HLI-induced transcriptional and epigenetic enrichment for inflammatory (NLRP3 inflammasome) and aging-associated (Neogenin-1, Thrombospondin-1) signatures in subsets of monocyte/dendritic progenitors. HLI-accelerated tumor growth and myeloid-skewing was transmissible via bone marrow transplantation, indicating long-term reprogramming of innate immune responses. Conclusions: Peripheral ischemia promotes inflammaging of HSCs and long-lasting alterations to anti-tumoral immunity, accelerating breast tumor growth.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557825,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9685,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":669818,"name":"José Gabriel Barcia Durán","orcid":"0000-0003-4764-5503","position":1,"is_corresponding":false},{"id":642779,"name":"Richard Von Itter","orcid":"0000-0001-8081-8328","position":2,"is_corresponding":false},{"id":1392827,"name":"Jessie M. Dalman","orcid":"0009-0003-9373-7035","position":3,"is_corresponding":false},{"id":458560,"name":"Brian Lim","orcid":"0000-0002-9074-0330","position":4,"is_corresponding":false},{"id":865668,"name":"Morgane Gourvest","orcid":"0000-0003-4095-6691","position":5,"is_corresponding":false},{"id":567590,"name":"Tarik Zahr","orcid":"0000-0002-2754-6092","position":6,"is_corresponding":false},{"id":348614,"name":"Kristin M. Wang","orcid":"0000-0002-2108-9900","position":7,"is_corresponding":false},{"id":425020,"name":"Tracy Zhang","orcid":"0000-0002-4325-8533","position":8,"is_corresponding":false},{"id":1393342,"name":"Noah Albarracin","orcid":null,"position":9,"is_corresponding":false},{"id":1383398,"name":"Whitney G. Rubin","orcid":null,"position":10,"is_corresponding":false},{"id":561760,"name":"Fazli Bozal","orcid":"0000-0002-5181-2274","position":11,"is_corresponding":false},{"id":866580,"name":"Michael Gildea","orcid":null,"position":12,"is_corresponding":false},{"id":236646,"name":"Coen van Solingen","orcid":"0000-0002-5817-2003","position":13,"is_corresponding":false},{"id":236657,"name":"Kathryn J. Moore","orcid":"0000-0003-2505-2547","position":14,"is_corresponding":false},{"id":236644,"name":"Alexandra Newman","orcid":"0000-0001-8938-2428","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T02:55:21.727661Z","pmid":"40654831","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}