Faculty Bibliography

BACKGROUND:Patients with peripheral artery disease have an 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 and cancer, but their contributions to cardiovascular disease-driven tumor progression are unclear. OBJECTIVES/OBJECTIVE:This study sought to study tumor growth after peripheral ischemia and consequent changes within the HSPC bone marrow compartment to uncover mechanisms through which altered hematopoiesis promotes cancer. METHODS:Mammary cancer (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 assay for transposase-accessible chromatin sequencing of bone marrow progenitors was performed to assess the distinct and synergistic transcriptomic and epigenetic changes of cancer and peripheral ischemia. 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. This was associated with accelerated cancer growth and enrichment of tumors with myeloid cells (monocytes, macrophages, neutrophils) and regulatory T cells. Increased myelopoiesis was also supported by sequencing analyses showing HLI and tumor-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 enhances inflammaging of hematopoietic stem cells and long-lasting alterations to antitumoral immunity, accelerating breast tumor growth.

The mammalian brain is the most cholesterol-rich organ of the body, relying on in situ de novo cholesterol synthesis. Maintaining cholesterol homeostasis is crucial for normal brain function. Oxysterol-binding protein (OSBP)-related proteins (ORPs) are highly conserved cytosolic proteins that coordinate lipid homeostasis by regulating cell signaling, inter-organelle membrane contact sites, and non-vesicular transport of cholesterol. Here, we show that ORP6 is highly enriched in the mammalian brain, particularly within neurons and astrocytes, with widespread expression across distinct brain regions, including the hippocampus, which is essential for learning and memory. Whole-body ablation of ORP6 (Osbpl6^-/-) in mice resulted in dysregulation of systemic and brain lipid homeostasis, with elevated levels of brain desmosterol and amyloid-beta oligomers (AβOs). Mechanistically, ORP6 knockdown in astrocytes altered the expression of cholesterol metabolism genes, promoting the accumulation of esterified cholesterol in lipid droplets, reducing cholesterol efflux and plasma membrane cholesterol content, and increasing amyloid-beta precursor protein (APP) processing. Our findings underscore the role of ORP6 in systemic and brain lipid homeostasis, highlighting its importance in maintaining overall brain health.

AIM/OBJECTIVE:To investigate how psychosocial stress contributes to accelerated thrombosis, focusing on platelet activation and hyperreactivity. The specific objective was to identify novel platelet regulators involved in stress-mediated thrombosis, with a particular emphasis on the tetraspanin CD37. METHODS AND RESULTS/RESULTS:To explore how stress contributes to platelet hyperreactivity, platelets were isolated from (1) mice that experienced chronic variable stress and stress-free controls (n=8/group) and (2) human subjects with self-reported high and no stress levels (n=18/group), followed by RNA-sequencing. By comparing mutually expressed transcripts, a subset of genes differentially expressed following psychosocial stress was identified in both human and mouse platelets. In both mice and humans, platelet CD37 positively associates with platelet aggregation responses that underlie thrombosis, with Cd37-/- platelets exhibiting impaired integrin αIIbβ3 signaling, characterized by reduced platelet fibrinogen spreading and decreased agonist-induced αIIbβ3 activation. Consistent with a role for CD37 in regulating platelet activation responses, chimeric mice that received Cd37-/- bone marrow experienced a significantly increased time to vessel occlusion in the carotid artery FeCl3 model compared to mice reconstituted with wild-type bone marrow. CD37 deficiency did not alter hemostasis, as platelet count, coagulation metrics, prothrombin time, and partial thromboplastin time did not differ in Cd37-/- mice relative to wild-type mice. Consistent with this, bleeding time did not differ between wild-type and Cd37-/- mice following tail tip transection. CONCLUSIONS:This study provides new insights into the platelet-associated mechanisms underlying stress-mediated thrombosis. Identifying CD37 as a novel regulator of platelet activation responses offers potential therapeutic targets for reducing the thrombotic risk associated with psychosocial stress. The findings also contribute to understanding how psychosocial stress accelerates thrombotic events and underscore the importance of platelet activation in this process.

Heart failure (HF) often coexists with cancer. Beyond the known cardiotoxicity of some cancer treatments, HF itself has been associated with increased cancer incidence. The 2 conditions share common risk factors, mechanisms, and interactions that can worsen patient outcomes. The bidirectional relationship between HF and cancer presents a complex interplay of factors that are not fully understood. Recent preclinical evidence suggests that HF may promote tumor growth via the release of protumorigenic factors from the injured heart, revealing HF as a potentially protumorigenic condition. Our review discusses the biological crosstalk between HF and cancer, emphasizing the impact of HF on tumor growth, with inflammation, and modulating the immune system as central mechanisms. We further explore the clinical implications of this connection and propose future research directions. Understanding the mechanistic overlap and interactions between HF and cancer could lead to new biomarkers and therapies, addressing the growing prevalence of both conditions and enhancing approaches to diagnosis, prevention, and treatment.

The field of cardio-oncology has traditionally focused on the impact of cancer and its therapies on cardiovascular health. Mounting clinical and preclinical evidence, however, indicates that the reverse may also be true: cardiovascular disease can itself influence tumor growth and metastasis. Numerous epidemiological studies have reported that individuals with prevalent cardiovascular disease have an increased incidence of cancer. In parallel, studies using preclinical mouse models of myocardial infarction, heart failure, and cardiac remodeling support the notion that cardiovascular disorders accelerate the growth of solid tumors and metastases. These findings have ushered in a new and burgeoning field termed reverse cardio-oncology that investigates the impact of cardiovascular disease pathophysiology on cancer emergence and progression. Recent studies have begun to illuminate the mechanisms driving this relationship, including shared risk factors, reprogramming of immune responses, changes in gene expression, and the release of cardiac factors that result in selective advantages for tumor cells or their local milieu, thus exacerbating cancer pathology. Here, we review the evidence supporting the relationship between cardiovascular disease and cancer, the mechanistic pathways enabling this connection, and the implications of these findings for patient care.

The discovery of long non-coding RNAs (lncRNAs) has provided a new perspective on the centrality of RNA in gene regulation and genome organization. Here, we screened for lncRNAs with putative functions in the host response to single-stranded RNA respiratory viruses. We identify CARINH as a conserved cis-acting lncRNA up-regulated in three respiratory diseases to control the expression of its antisense gene IRF1, a key transcriptional regulator of the antiviral response. CARINH and IRF1 are coordinately increased in the circulation of patients infected with human metapneumovirus, influenza A virus, or SARS-CoV-2, and in macrophages in response to viral infection or TLR3 agonist treatment. Targeted depletion of CARINH or its mouse ortholog Carinh in macrophages reduces the expression of IRF1/Irf1 and their associated target gene networks, increasing susceptibility to viral infection. Accordingly, CRISPR-mediated deletion of Carinh in mice reduces antiviral immunity, increasing viral burden upon sublethal challenge with influenza A virus. Together, these findings identify a conserved role of lncRNA CARINH in coordinating interferon-stimulated genes and antiviral immune responses.

BACKGROUND & AIMS/UNASSIGNED:Metabolic syndrome-associated steatotic liver disease (MASLD) and metabolic syndrome-associated steatohepatitis (MASH) have global prevalence rates exceeding 25% and 3-6%, respectively. The introduction of high-fructose corn syrup to the diet in the 1970s has been linked to metabolic and hepatic disturbances. Despite these associations, the potential for sex-dependent responses resulting from fructose-containing diets on MASLD/MASH has not been addressed. METHODS/UNASSIGNED:standard chow for 16 weeks (n = 40 mice). At sacrifice, plasma and liver were retrieved, the latter for single-nucleus RNA sequencing. Publicly available data sets of human male and female MASH liver were probed. RESULTS/UNASSIGNED:0.0001). Single-nucleus RNA sequencing revealed distinct sex-specific transcriptional profiles in hepatocytes and stellate cells responding to the FPC-NASH diet compared to the standard chow. In female mice, compared to males, pathways associated with lipid and metabolic processes in hepatocytes and cell-cell communication and adhesion in stellate cells were enriched. Metabolic flux analyses demonstrated reduced bile acid metabolism in female mice and human hepatocytes in FPC-NASH and MASH conditions, respectively, compared to their male counterparts. CONCLUSIONS/UNASSIGNED:Molecular profiling of hepatocytes and stellate cells in FPC-NASH diet-fed mice revealed significant sex differences mirrored in human MASH. The identification of intrinsic, within-sex, diet-dependent disparities underscores the critical need to include both male and female individuals in MAFLD/MASH studies and clinical trials. IMPACT AND IMPLICATIONS/UNASSIGNED:male patients with MASH. These results highlight potential mechanistic explanations and therapeutic targets for addressing sex differences and underscore the need to study both sexes in animal models and human MASH.

Immune checkpoint inhibitor (ICI) therapies can increase the risk of cardiovascular events in survivors of cancer by worsening atherosclerosis. Here we map the expression of immune checkpoints (ICs) within human carotid and coronary atherosclerotic plaques, revealing a network of immune cell interactions that ICI treatments can unintentionally target in arteries. We identify a population of mature, regulatory CCR7⁺FSCN1⁺ dendritic cells, similar to those described in tumors, as a hub of IC-mediated signaling within plaques. Additionally, we show that type 2 diabetes and lipid-lowering therapies alter immune cell interactions through PD-1, CTLA4, LAG3 and other IC targets in clinical development, impacting plaque inflammation. This comprehensive map of the IC interactome in healthy and cardiometabolic disease states provides a framework for understanding the potential adverse and beneficial impacts of approved and investigational ICIs on atherosclerosis, setting the stage for designing ICI strategies that minimize cardiovascular disease risk in cancer survivors.

Atherosclerosis results from lipid-driven inflammation of the arterial wall that fails to resolve. Imbalances in macrophage accumulation and function, including diminished migratory capacity and defective efferocytosis, fuel maladaptive inflammation and plaque progression. The neuroimmune guidance cue netrin-1 has dichotomous roles in inflammation partly due to its multiple receptors; in atherosclerosis, netrin-1 promotes macrophage survival and retention via its receptor Unc5b. To minimize the pleiotropic effects of targeting netrin-1, we tested the therapeutic potential of deleting Unc5b in mice with advanced atherosclerosis. We generated Unc5b