The role of lipid metabolism in cancer radioresistance

Abstract Obesity is one of the most serious global health problems, with an incidence that increases yearly and coincides with the development of cancer. Adipose tissue macrophages (ATMs) are particularly important in this context and contribute to linking obesity-related inflammation and tumor progression. However, the functions of ATMs on the progression of obesity-associated cancer remain unclear. In this review, we describe the origins, phenotypes, and functions of ATMs. Subsequently, we summarize the potential mechanisms on the reprogramming of ATMs in the obesity-associated microenvironment, including the direct exchange of dysfunctional metabolites, inordinate cytokines and other signaling mediators, transfer of extracellular vesicle cargo, and variations in the gut microbiota and its metabolites. A better understanding of the properties and functions of ATMs under conditions of obesity will lead to the development of new therapeutic interventions for obesity-related cancer. 

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Adipose tissue macrophages: implications for obesity-associated cancer

Functional states of myeloid cells in cancer

Background: An increasing number of studies suggest that diet plays an important role in regulating aging processes and modulates the development of the most important age-related diseases. Objective: The aim of this review is to provide an overview of the relationship between nutrition and critical age-associated diseases. Methods: A literature review was conducted to survey recent pre-clinical and clinical findings related to the role of nutritional factors in modulation of fundamental cellular and molecular mechanisms of aging and their role in prevention of the genesis of the diseases of aging. Results: Studies show that the development of cardiovascular and cerebrovascular diseases, neurodegenerative diseases, cognitive impairment and dementia can be slowed down or prevented by certain diets with anti-aging action. The protective effects of diets, at least in part, may be mediated by their beneficial macro- (protein, fat, carbohydrate) and micronutrient (vitamins, minerals) composition. Conclusions: Certain diets, such as the Mediterranean diet, may play a significant role in healthy aging by preventing the onset of certain diseases and by improving the aging process itself. This latter can be strengthened by incorporating fasting elements into the diet. As dietary recommendations change with age, this should be taken into consideration as well, when developing a diet tailored to the needs of elderly individuals. Future and ongoing clinical studies on complex anti-aging dietary interventions translating the results of preclinical investigations are expected to lead to novel nutritional guidelines for older adults in the near future.

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Nutrition Strategies Promoting Healthy Aging: From Improvement of Cardiovascular and Brain Health to Prevention of Age-Associated Diseases

Immune responses in nonlymphoid tissues play a vital role in the maintenance of homeostasis. Lots of evidence supports that tissue-specific immune cells provide defense against tumor through the localization in different tissue throughout the body, and can be regulated by diverse factors. Accordingly, the distribution of nervous tissue is also tissue-specific which is essential in the growth of corresponding organs, and the occurrence and development of tumor. Although there have been many mature perspectives on the neuroendocrine regulation in tumor microenvironment, the neuroendocrine regulation of tissue-specific immune cells has not yet been summarized. In this review, we focus on how tissue immune responses are influenced by autonomic nervous system, sensory nerves, and various neuroendocrine factors and reversely how tissue-specific immune cells communicate with neuroendocrine system through releasing different factors. Furthermore, we pay attention to the potential mechanisms of neuroendocrine-tissue specific immunity axis involved in tumors. This may provide new insights for the immunotherapy of tumors in the future.

Neuroendocrine regulations in tissue-specific immunity: From mechanism to applications in tumor

Nutriments have been deemed to impact all physiopathologic processes. Recent evidences in molecular medicine and clinical trials have demonstrated that adequate nutrition treatments are the golden criterion for extending healthspan and delaying ageing in various species such as yeast, drosophila, rodent, primate and human. It emerges to develop the precision-nutrition therapeutics to slow age-related biological processes and treat diverse diseases. However, the nutritive advantages frequently diversify among individuals as well as organs and tissues, which brings challenges in this field. In this review, we summarize the different forms of dietary interventions extensively prescribed for healthspan improvement and disease treatment in pre-clinical or clinical. We discuss the nutrient-mediated mechanisms including metabolic regulators, nutritive metabolism pathways, epigenetic mechanisms and circadian clocks. Comparably, we describe diet-responsive effectors by which dietary interventions influence the endocrinic, immunological, microbial and neural states responsible for improving health and preventing multiple diseases in humans. Furthermore, we expatiate diverse patterns of dietotheroapies, including different fasting, calorie-restricted diet, ketogenic diet, high-fibre diet, plants-based diet, protein restriction diet or diet with specific reduction in amino acids or microelements, potentially affecting the health and morbid states. Altogether, we emphasize the profound nutritional therapy, and highlight the crosstalk among explored mechanisms and critical factors to develop individualized therapeutic approaches and predictors. 

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Dietary regulation in health and disease

ABSTRACT The tumor-adipose microenvironment (TAME) is a universal microecosystem, that is characterized by the dysfunction of lipid metabolism, such as excessive free fatty acids (FFAs). Macrophages are the most abundant immune cell type within TAME, although their diversity in the TAME is not clear. We first reveal that infiltration of M2-like macrophages in the TAME is associated with poor survival in breast cancer. To explore lipid-associated alterations in the TAME, we also detected the levels of FFAs transporters including fatty acid binding proteins (FABPs) and fatty acid transport protein 1 (FATP1). The results indicated that expression of fatty acid transporters in the TAME is tightly linked to the function of macrophages and predicts survival in breast cancer. To explore the impact of FFAs transporters on the function of macrophages, we performed single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. Consequently, we identified a special subpopulation of macrophages defined as lipid-associated macrophages (LAMs), highly expressed macrophage markers (CD163, SPP1 and C1QC), genes involved in lipid metabolism (FABP3, FABP4, FABP5, LPL and LIPA) and some lipid receptors (LGALS3 and TREM2). Functionally, LAMs were characterized by a canonical functional signature of M2-like macrophages, lipid accumulation and enhancing phagocytosis, and they were mostly distributed in tumor-adipose junctional regions. Finally, the allograft cancer mouse models confirmed that LAMs depletion in the TAME synergizes the antitumorigenic effects of anti-PD1 therapy. In summary, we defined a novel subtype of macrophages in the TAME, that has unique features and clinical outcomes.

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2022.2085432?needAccess=true

Lipid-associated macrophages in the tumor-adipose microenvironment facilitate breast cancer progression

The heterogeneity and the complex cellular architecture have a crucial effect on breast cancer progression and response to treatment. However, deciphering the neoplastic subtypes and their spatial organization is still challenging. Here, we combine single-nucleus RNA sequencing (snRNA-seq) with a microarray-based spatial transcriptomics (ST) to identify cell populations and their spatial distribution in breast cancer tissues. Malignant cells are clustered into distinct subpopulations. These cell clusters not only have diverse features, origins and functions, but also emerge to the crosstalk within subtypes. Furthermore, we find that these subclusters are mapped in distinct tissue regions, where discrepant enrichment of stromal cell types are observed. We also inferred the abundance of these tumorous subpopulations by deconvolution of large breast cancer RNA-seq cohorts, revealing differential association with patient survival and therapeutic response. Our study provides a novel insight for the cellular architecture of breast cancer and potential therapeutic strategies. 

/pdf/single-cell-and-spatially-resolved-analysis-uncovers-cell-1fdfs4v9.pdf

Single-cell and spatially resolved analysis uncovers cell heterogeneity of breast cancer

Cell omics such as single-cell genomics, proteomics and microbiomics allow the characterisation of tissue and microbial community composition, which can be compared between conditions to identify biological drivers. This strategy has been critical to unveiling markers of disease progression such as cancer and pathogen infection. For cell omic data, no method for differential variability analysis exists, and methods for differential composition analysis only take a few fundamental data properties into account. Here we introduce sccomp, a generalised method for differential composition and variability analyses able to jointly model data count distribution, compositionality, group-specific variability and proportion mean-variability association, with awareness against outliers. Sccomp is an extensive analysis framework that allows realistic data simulation and cross-study knowledge transfer. Here, we demonstrate that mean-variability association is ubiquitous across technologies showing the inadequacy of the very popular Dirichlet-multinomial modelling and provide mandatory principles for differential variability analysis. We show that sccomp accurately fits experimental data, with a 50% incremental improvement over state-of-the-art algorithms. Using sccomp, we identified novel differential constraints and composition in the microenvironment of primary breast cancer. Significance statement Determining the composition of cell populations is made possible by technologies like single-cell transcriptomics, CyTOF and microbiome sequencing. Such analyses are now widespread across fields (~800 publications/month, Scopus). However, existing methods for differential abundance do not model all data features, and cell-type/taxa specific differential variability is not yet possible. Increase in the variability of tissue composition and microbial communities is a well-known indicator of loss of homeostasis and disease. A suitable statistical method would enable new types of analyses to identify component-specific loss of homeostasis for the first time. This and other innovations are now possible through our discovery of the mean-variability association for compositional data. Based on this fundamental observation, we have developed a new statistical model, sccomp, that enables differential variability analysis for composition data, improved differential abundance analyses, with cross-sample information borrowing, outlier identification and exclusion, realistic data simulation, based on experimental datasets, cross-study knowledge transfer.

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Robust differential composition and variability analysis for multisample cell omics

Macrolide antibiotics are widely used antibacterial agents that are associated with autophagy inhibition. This study aimed to investigate the association between macrolide antibiotics and malignant tumors, as well as the effect on autophagy, reactive oxygen species (ROS) accumulation and integrated stress response (ISR). The meta-analysis indicated a modestly higher risk of cancer in macrolide antibiotic ever-users compared to non-users. Further experiments showed that macrolides block autophagic flux by inhibiting lysosomal acidification. Additionally, azithromycin, a representative macrolide antibiotic, induced the accumulation of ROS, and stimulated the ISR and the activation of transcription factor EB (TFEB) and TFE3 in a ROS-dependent manner. Finally, animal experiments confirmed that azithromycin promoted tumor progression in vivo, which could be receded by N-acetylcysteine, an inhibitor of ROS and ISR. Overall, this study reveals the potential role of macrolide antibiotics in malignant progression and highlights the need for further investigation into their effects.

/pdf/macrolide-antibiotics-activate-the-integrated-stress-1xlf1por.pdf

Z. Gao

Papers

Dietary regulation in health and disease

Lipid-associated macrophages in the tumor-adipose microenvironment facilitate breast cancer progression

Single-cell and spatially resolved analysis uncovers cell heterogeneity of breast cancer

Robust differential composition and variability analysis for multisample cell omics

Macrolide antibiotics activate the integrated stress response and promote tumor proliferation