Ischemic Injury Drives Tumor Growth via Accelerated Hematopoietic Aging

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: Peripheral ischemia increased monocyte and neutrophil output at the expense of lymphocytes, driven by a shift toward CD150hi 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.