Dalman, J. M. | bioRxiv Science

bioRxiv2025

Ischemic Injury Drives Tumor Growth via Accelerated Hematopoietic Aging

BackgroundPatients 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. ObjectivesTo study cancer growth following peripheral ischemia and consequent changes within the HSPC bone marrow compartment to uncover mechanisms through which altered hematopoiesis promotes oncogenesis. MethodsMammary 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. ResultsPeripheral 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. ConclusionsPeripheral ischemia promotes inflammaging of HSCs and long-lasting alterations to anti-tumoral immunity, accelerating breast tumor growth.

immunology↗

bioRxiv2025

An immunocompetent mouse model of liposarcoma

Liposarcoma (LPS) is the most prevalent soft tissue sarcoma. The most common biological subtypes are well-differentiated (WDLPS), a low-grade disease that can evolve to high-grade dedifferentiated liposarcoma (DDLPS), with increased rates of recurrence and metastasis and low response rates to systemic therapies. Preclinical testing of immunotherapeutics for LPS has been held back by the lack of an immunocompetent mouse model. Here, we present an autochthonous immunocompetent LPS mouse model, ACPP, with targeted deletion of Trp53 and Pten in adipocytes to mimic signaling alterations observed in human LPS. Similar to humans, ACPP mice produce WDLPS, DDLPS, and tumors that exhibit both WD and DD components. Murine and human DDLPS tumors possess transcriptional similarities, including increased expression of oncogenes Cdk4 and Hmga2 and reduced expression of the tumor suppressor Cebpa; furthermore, both mouse and human DDLPS exhibit heterogenous T cell infiltration. Syngeneic cell lines derived from ACPP DDLPS reliably produce tumors following orthotopic implantation, each with distinct growth patterns, aggressiveness, and immune profiles. These unique models provide much needed tools to understand the complex immunobiology of LPS and greatly accelerate the pace of preclinical studies aimed at uncovering more effective new therapies for patients with this aggressive malignancy.

cancer biology↗