Explore the vast range of titles available.

Somatic copy number alterations (SCNAs) are prevalent in cancer and play a significant role in both tumorigenesis and therapeutic resistance. While focal SCNAs have been extensively studied, the impact of larger arm-level SCNAs remains poorly understood. Here, we investigated the association between arm-level SCNAs and overall survival in triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer lacking targeted therapies. We identified frequent arm-level SCNAs, including 21q gain and 7p gain, which correlated with poor overall survival in TNBC patients. Further, we identified the expression of specific genes within these SCNAs associated with survival. Notably, we found that the expression of RIPK4 , a gene located on 21q, exhibited a strong correlation with poor overall survival. In functional assays, we demonstrated that targeting Ripk4 in a murine lung metastatic TNBC model significantly reduced tumor burden, improved survival, and increased CD4 + and CD8 + T cell infiltration. RIPK4 enhanced the survival of triple-negative breast cancer cells at secondary sites, thereby facilitating the formation of metastatic lesions. Our findings highlight the significance of arm-level SCNAs in breast cancer progression and identify RIPK4 as a putative driver of TNBC metastasis and immunosuppression.

Metastasis is the predominant cause of cancer-related mortality, despite being a highly inefficient process overall. The vasculature is the gatekeeper for tumor cell seeding within the secondary tissue microenvironment-the rate limiting step of the metastatic cascade. Therefore, factors that regulate vascular physiology dramatically influence cancer outcomes. There are a myriad of physiologic circumstances that not only influence the intrinsic capacity of tumor cells to cross the endothelial barrier, but also that regulate vascular inflammation and barrier integrity to enable extravasation into the metastatic niche. These processes are highly dependent on inflammatory cues largely initiated by the innate immune compartment, that are meant to help re-establish tissue homeostasis, but instead become hijacked by cancer cells. Here, we discuss the scientific advances in understanding the interactions between innate immune cells and the endothelium, describe their influence on cancer metastasis, and evaluate potential therapeutic interventions for the alleviation of metastatic disease. By triangulating the relationship between immune cells, endothelial cells, and tumor cells, we will gain greater insight into how to impede the metastatic process by focusing on its most vulnerable phases, thereby reducing metastatic spread and cancer-related mortality.

Metastasis is the leading cause of cancer-related deaths, and obesity is associated with increased breast cancer (BC) metastasis. Preclinical studies have shown that obese adipose tissue induces lung neutrophilia associated with enhanced BC metastasis to this site. Here we show that obesity leads to neutrophil-dependent impairment of vascular integrity through loss of endothelial adhesions, enabling cancer cell extravasation into the lung. Mechanistically, neutrophil-produced reactive oxygen species in obese mice increase neutrophil extracellular DNA traps (NETs) and weaken endothelial junctions, facilitating the influx of tumor cells from the peripheral circulation. In vivo treatment with catalase, NET inhibitors or genetic deletion of Nos2 reversed this effect in preclinical models of obesity. Imaging mass cytometry of lung metastasis samples from patients with cancer revealed an enrichment in neutrophils with low catalase levels correlating with elevated body mass index. Our data provide insights into potentially targetable mechanisms that underlie the progression of BC in the obese population. Quail and colleagues demonstrate that neutrophil-derived ROS and extracellular traps (NETs) mediate breast cancer metastasis to the lungs by altering endothelial junctional adhesions, thus favoring vascular permeability and transendothelial migration of cancer cells.

There is active crosstalk between tumor cells and the tumor microenvironment during metastatic progression, a process that is significantly affected by obesity, particularly in breast cancer. Here we analyze the impact of a high fat diet (HFD) on metastasis, focusing on the role of platelets in the formation of premetastatic niches (PMNs). We find that a HFD provokes pre-activation of platelets and endothelial cells, promoting the formation of PMNs in the lung. These niches are characterized by increased vascular leakiness, platelet activation and overexpression of fibronectin in both platelets and endothelial cells. A HFD promotes interactions between platelets, tumor cells and endothelial cells within PMNs, enhancing tumor cell homing and metastasis. Importantly, therapeutic interventions like anti-platelet antibody administration or a dietary switch reduce metastatic cell homing and outgrowth. Moreover, blocking fibronectin reduces the interaction of tumor cells with endothelial cells. Importantly, when coagulation parameters prior to neoadjuvant treatment are considered, triple negative breast cancer (TNBC) female patients with reduced Partial Thromboplastin time (aPTT) had a significantly shorter time to relapse. These findings highlight how diet and platelet activation in pre-metastatic niches affect tumor cell homing and metastasis, suggesting potential therapeutic interventions and prognostic markers for TNBC patients. Previous work has identified a link between obesity and breast cancer metastasis. Here, using preclinical mouse models, the authors show that high-fat diet promotes platelet and endothelial cell activation in the lungs resulting in the development premetastatic niches, enhancing tumor cell homing and metastasis.

BackgroundImmunotherapy has revolutionized clinical outcomes for patients suffering from lung cancer, yet relatively few patients sustain long-term durable responses. Recent studies have demonstrated that the tumor immune microenvironment fosters tumorous heterogeneity and mediates both disease progression and response to immune checkpoint inhibitors (ICI). As such, there is an unmet need to elucidate the spatially defined single-cell landscape of the lung cancer microenvironment to understand the mechanisms of disease progression and identify biomarkers of response to ICI.MethodsHere, in this study, we applied imaging mass cytometry to characterize the tumor and immunological landscape of immunotherapy response in non-small cell lung cancer by describing activated cell states, cellular interactions and neighborhoods associated with improved efficacy. We functionally validated our findings using preclinical mouse models of cancer treated with anti-programmed cell death protein-1 (PD-1) immune checkpoint blockade.ResultsWe resolved 114,524 single cells in 27 patients treated with ICI, enabling spatial resolution of immune lineages and activation states with distinct clinical outcomes. We demonstrated that CXCL13 expression is associated with ICI efficacy in patients, and that recombinant CXCL13 potentiates anti-PD-1 response in vivo in association with increased antigen experienced T cell subsets and reduced CCR2+ monocytes.DiscussionOur results provide a high-resolution molecular resource and illustrate the importance of major immune lineages as well as their functional substates in understanding the role of the tumor immune microenvironment in response to ICIs.

Obesity affects ~30% of adults in North America and is linked to greater incidence and relative risk of death from cancer across multiple tumor types, such as breast cancer. Interestingly, normal weight individuals can exhibit metabolic obesity, which accounts for ~20% of normal weight individuals, highlighting the complexity of the underlying biological mechanisms at play. Obesity is associated with alterations in the immune repository, including myeloid cell types. Using both diet-induced and genetic preclinical models of obesity, it has been previously shown that obesity causes alterations in myeloid cell populations, which enhance cancer growth and metastasis. However, the mechanisms underlying how obesity regulates myeloid cell populations to influence cancer progression have never been formally addressed. The objective of my doctoral thesis is to characterize the effects of obesity-associated inflammation on tumor immunology, including within the local tumor microenvironment, systemically within the circulation, and within secondary metastatic niches, specifically the lung. I hypothesize that obesity regulates myeloid cell function to coordinate processes that support tumor progression, including enhanced primary tumor growth and enhanced cancer metastasis. My doctoral research has shown that (a) within the local tumor microenvironment, obesity increases primary tumor growth through local inflammatory changes within the adipose tissue niche, including aberrant activation of macrophages. I have found that these effects can be reversed, in part, by altering the metabolism of adipocytes, through the process of thermogenesis. Beyond the primary niche, I have discovered that (b) inflammatory changes within adipose tissue have subsequent systemic effects in obese hosts, including alterations to various myeloid populations such as neutrophils and monocytes. I have found that these observations occur as a result of shifts in hematopoietic developmental trajectories that occur with obesity. Mechanistically, obesity enhances neutrophilia from granulocyte-monocyte progenitors (GMPs) to produce mature neutrophils at the expense of GMP-derived Ly6C hi monocytes. To compensate, Ly6C hi monocytes become enriched from monocyte-dendritic cell progenitors (MDPs) to favour a monocyte-dendritic cell (moDC) fate, whereas lean hosts exhibit Ly6C himonocyte expansion primarily from GMPs. Consequentially, I have discovered that (c) these systemic inflammatory alterations lead to a disruption in homeostasis in distant tissue niches devoid of adipocytes, such as the lung, leading to enhanced extravasation and metastasis to this site. I have found that changes within the tissue microenvironment go beyond the immune compartment, including the quality of the vasculature. Mechanistically, obesity reprograms neutrophils to produce elevated levels of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) which act on the vasculature to weaken the integrity of the endothelium, driving cancer cell extravasation. Given that obesity is increasing worldwide, understanding the mechanistic relationship between obesity-associated inflammation and cancer is of great clinical importance. Further, given that obesity drives broad systemic immune alterations, these findings may have wide-ranging implications for other obesity-associated comorbidities

High-parameter multiplex immunostaining techniques have revolutionized our ability to image healthy and diseased tissues with unprecedented depth; however, accurate cell identification and segmentation remain significant downstream challenges. Identifying individual cells with high precision is a requisite to reliably and reproducibly interpret acquired data. Here we introduce CIRCLE, a cell identification pipeline that combines classical and modern machine learning-based computer vision algorithms to address the shortcomings of current cell segmentation tools for 2D images. CIRCLE is a fully automated hybrid cell detection model, eliminating subjective investigator bias and enabling high-throughput image analysis. CIRCLE accurately distinguishes cells across diverse tissues microenvironments, resolves low-resolution structures, and can be applied to any 2D image that contains nuclei. Importantly, we quantitatively demonstrate that CIRCLE outperforms current state-of-the-art image segmentation tools using multiple accuracy measures. As high-throughput multiplex imaging grows closer toward standard practice for histology, integration of CIRCLE into analysis protocols will deliver unparalleled segmentation quality. Competing Interest Statement The authors have declared no competing interest.