The tumor-promoting potential of CCL5 has been proposed but remains poorly understood. We demonstrate here that an autocrine CCL5-CCR5 axis is a major regulator of immunosuppressive myeloid cells ...(IMC) of both monocytic and granulocytic lineages. The absence of the autocrine CCL5 abrogated the generation of granulocytic myeloid-derived suppressor cells and tumor-associated macrophages. In parallel, enhanced maturation of intratumoral neutrophils and macrophages occurred in spite of tumor-derived CCL5. The refractory nature of
-null myeloid precursors to tumor-derived CCL5 was attributable to their persistent lack of membrane-bound CCR5. The changes in the
-null myeloid compartment subsequently resulted in increased tumor-infiltrating cytotoxic CD8
T cells and decreased regulatory T cells in tumor-draining lymph nodes. An analysis of human triple-negative breast cancer specimens demonstrated an inverse correlation between "immune CCR5" levels and the maturation status of tumor-infiltrating neutrophils as well as 5-year-survival rates. Targeting the host CCL5 in bone marrow via nanoparticle-delivered expression silencing, in combination with the CCR5 inhibitor Maraviroc, resulted in strong reductions of IMC and robust antitumor immunities. Our study suggests that the myeloid CCL5-CCR5 axis is an excellent target for cancer immunotherapy.
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Aberrant metabolism is the root cause of several serious health issues, creating a huge burden to health and leading to diminished life expectancy. A dysregulated metabolism induces the secretion of ...several molecules which in turn trigger the inflammatory pathway. Inflammation is the natural reaction of the immune system to a variety of stimuli, such as pathogens, damaged cells, and harmful substances. Metabolically triggered inflammation, also called metaflammation or low-grade chronic inflammation, is the consequence of a synergic interaction between the host and the exposome-a combination of environmental drivers, including diet, lifestyle, pollutants and other factors throughout the life span of an individual. Various levels of chronic inflammation are associated with several lifestyle-related diseases such as diabetes, obesity, metabolic associated fatty liver disease (MAFLD), cancers, cardiovascular disorders (CVDs), autoimmune diseases, and chronic lung diseases. Chronic diseases are a growing concern worldwide, placing a heavy burden on individuals, families, governments, and health-care systems. New strategies are needed to empower communities worldwide to prevent and treat these diseases. Precision medicine provides a model for the next generation of lifestyle modification. This will capitalize on the dynamic interaction between an individual's biology, lifestyle, behavior, and environment. The aim of precision medicine is to design and improve diagnosis, therapeutics and prognostication through the use of large complex datasets that incorporate individual gene, function, and environmental variations. The implementation of high-performance computing (HPC) and artificial intelligence (AI) can predict risks with greater accuracy based on available multidimensional clinical and biological datasets. AI-powered precision medicine provides clinicians with an opportunity to specifically tailor early interventions to each individual. In this article, we discuss the strengths and limitations of existing and evolving recent, data-driven technologies, such as AI, in preventing, treating and reversing lifestyle-related diseases.
Patients with triple-negative breast cancers (TNBC) are at high risk for recurrence and metastasis at an early time despite standard treatment, underscoring the need for novel therapeutic modalities. ...Here, we report for the first time a distinctive and profound role of the E3 ubiquitin ligase UBR5 in the growth and metastasis of TNBC. An analysis of primary TNBC specimen by whole-exon sequencing revealed strong gene amplifications of UBR5 associated with the disease. UBR5 overexpression in TNBC tissues was confirmed at mRNA and protein levels. CRISPR/Cas9-mediated deletion of ubr5 in an experimental murine mammary carcinoma model of TNBC dramatically abrogated tumor growth and metastasis
, which could be reversed completely via reconstitution with wild-type UBR5 but not a catalytically inactive mutant. Loss of UBR5 caused an impairment in angiogenesis within the tumor, associated with increased apoptosis, necrosis, and growth arrest. Absence of UBR5 in the tumor triggered aberrant epithelial-to-mesenchymal transition, principally via abrogated expression of E-cadherin, which resulted in severely reduced tumor metastasis to secondary organs. Use of NOD/SCID mice revealed that tumor-derived UBR5 facilitated tumor growth in a manner completely dependent upon immune cells in the microenvironment, whereas it promoted metastasis in a tumor cell-autonomous fashion. Our findings unveil UBR5 as a novel and critical regulator of tumor growth, metastasis, and immune response and highlight the potential for UBR5 as an effective therapeutic target for the treatment of highly aggressive breast and ovarian cancers that fail conventional therapy.
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The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression ...and metastasis. The significance of endothelial cells (ECs) in this scenario was initially attributed to their role in vasculogenesis and angiogenesis that is critical for tumor initiation and growth. Nevertheless, the identification of endothelial-derived angiocrine factors illustrated an alternative non-angiogenic function of ECs contributing to both physiological and pathological tissue development. Gene expression profiling studies have demonstrated distinctive expression patterns in tumor-associated endothelial cells that imply a bilateral crosstalk between tumor and its endothelium. Recently, some of the molecular determinants of this reciprocal interaction have been identified which are considered as potential targets for developing novel anti-angiocrine therapeutic strategies.
Tumor initiation and growth depend on its microenvironment in which cancer-associated fibroblasts （CAFs） in tumor stroma play an important role. Prostaglandin E2 （PGE2） and interleukin （IL）-6 signal ...pathways are involved in the crosstalk between tumor and stromal cells. However, how PGE2-mediated signaling modulates this crosstalk remains unclear. Here, we show that microRNA （miR）-149 links PGE2 and IL-6 signaling in mediating the crosstalk between tumor cells and CAFs in gastric cancer （GC）. miR-149 inhibited fibroblast activation by targeting IL-6 and miR-149 expression was substantially suppressed in the CAFs of GC. miR-149 negatively regulated CAFs and their effect on GC development both in vitro and in vivo. CAFs enhanced epithelial-to-mesenchymal transition （EMT） and the stem-like properties of GC cells in a miR-149-1L-6-dependent manner. In addition to IL-6, PGE2 receptor 2 （PTGER2/EP2） was revealed as another potential target of miR-149 in fibroblasts. Furthermore, H. pylori infection, a leading cause of human GC, was able to induce cyclooxygenase-2 （COX-2）/PGE2 signaling and to enhance PGE2 production, resulting in the hypermethylation of miR-149 in CAFs and increased IL-6 secretion. Our findings indicate that miR-149 mediates the crosstalk between tumor cells and CAFs in GC and highlight the potential of interfering miRNAs in stromal cells to improve cancer therapy.
Summary Breast cancer is a major health problem in both developing and developed countries. It is the most frequently diagnosed female malignant disease in Arab populations. The incidence of breast ...cancer is lower in Arab countries than in Europe and the USA but is rising fast. Breast cancers in women from Arab populations have different characteristics to those reported in individuals from Europe and the USA. For example, affected patients are at least a decade younger, they have a more advanced stage of disease at first presentation, and their tumour size is larger. Moreover, in some Arab populations, reports suggest increased axillary-lymph-node invasion, a larger proportion of negative hormone receptors, and a higher tumour grade. These disparities are not only confined to clinicopathological features but also exist at the molecular level, as shown by findings of genome-wide association studies and expression profiling.
Breast cancer (BC) is one of the most diagnosed cancers worldwide and is the second cause of cancer related death in women. The most frequent cause of BC-related deaths, like many cancers, is ...metastasis. However, metastasis is a complicated and poorly understood process for which there is a shortage of accurate prognostic indicators and effective treatments. With the rapid and ever-evolving development and application of genomic sequencing technologies, many novel molecules were identified that play previously unappreciated and important roles in the various stages of metastasis. In this review, we summarize current advancements in the functional genomic analysis of BC metastasis and discuss about the potential prognostic and therapeutic implications from the recent genomic findings.
Admixture mapping has been useful in identifying genetic variations linked to phenotypes, adaptation and diseases. Copy number variations (CNVs) represents genomic structural variants spanning large ...regions of chromosomes reaching several megabases. In this investigation, the "Canary" algorithm was applied to 102 Tunisian samples and 991 individuals from eleven HapMap III populations to genotype 1279 copy number polymorphisms (CNPs). In this present work, we investigate the Tunisian population structure using the CNP makers previously identified among Tunisian. The study revealed that Sub-Saharan African populations exhibited the highest diversity with the highest proportions of allelic CNPs. Among all the African populations, Tunisia showed the least diversity. Individual ancestry proportions computed using STRUCTURE analysis revealed a major European component among Tunisians with lesser contribution from Sub-Saharan Africa and Asia. Population structure analysis indicated the genetic proximity with Europeans and noticeable distance from the Sub-Saharan African and East Asian clusters. Seven genes harbouring Tunisian high-frequent CNPs were identified known to be associated with 9 Mendelian diseases and/or phenotypes. Functional annotation of genes under selection highlighted a noteworthy enrichment of biological processes to receptor pathway and activity as well as glutathione metabolism. Additionally, pathways of potential concern for health such as drug metabolism, infectious diseases and cancers exhibited significant enrichment. The distinctive genetic makeup of the Tunisians might have been influenced by various factors including natural selection and genetic drift, resulting in the development of distinct genetic variations playing roles in specific biological processes. Our research provides a justification for focusing on the exclusive genome organization of this population and uncovers previously overlooked elements of the genome.
Significant advances have been made to understand the genetic basis of breast cancer. High, moderate and low penetrance variants have been identified with inter-ethnic variability in mutation ...frequency and spectrum. Genome wide association studies (GWAS) are widely used to identify disease-associated SNPs. Understanding the functional impact of these risk-SNPs will help the translation of GWAS findings into clinical interventions. Here we aim to characterize the genetic patterns of high and moderate penetrance breast cancer susceptibility genes and to assess the functional impact of non-coding SNPs. We analyzed BRCA1/2, PTEN, STK11, TP53, ATM, BRIP1, CHEK2 and PALB2 genotype data obtained from 135 healthy participants genotyped using Affymetrix Genome-Wide Human SNP-Array 6.0. Haplotype analysis was performed using Haploview.V4.2 and PHASE.V2.1. Population structure and genetic differentiation were assessed using principal component analysis (PCA) and fixation index (FST). Functional annotation was performed using In Silico web-based tools including RegulomeDB and VARAdb. Haplotype analysis showed distinct LD patterns with high levels of recombination and haplotype blocks of moderate to small size. Our findings revealed also that the Tunisian population tends to have a mixed origin with European, South Asian and Mexican footprints. Functional annotation allowed the selection of 28 putative regulatory variants. Of special interest were BRCA1_ rs8176318 predicted to alter the binding sites of a tumor suppressor miRNA hsa-miR-149 and PALB2_ rs120963 located in tumorigenesis-associated enhancer and predicted to strongly affect the binding of P53. Significant differences in allele frequencies were observed with populations of African and European ancestries for rs8176318 and rs120963 respectively. Our findings will help to better understand the genetic basis of breast cancer by guiding upcoming genome wide studies in the Tunisian population. Putative functional SNPs may be used to develop an efficient polygenic risk score to predict breast cancer risk leading to better disease prevention and management.
Many cancers, including breast cancer, have demonstrated prognosis and support advantages thanks to the discovery of targeted therapies. The advent of these new approaches marked the rise of ...precision medicine, which leads to improve the diagnosis, prognosis and treatment of cancer. Precision medicine takes into account the molecular and biological specificities of the patient and their tumors that will influence the treatment determined by physicians. This new era of medicine is accessible through molecular genetics platforms, the development of high-speed sequencers and means of analysis of these data. Despite the spectacular results in the treatment of cancers including breast cancer, described in this review, not all patients however can benefit from this new strategy. This seems to be related to the many genetic mutations, which may be different from one patient to another or within the same patient. It comes to give new impetus to the research-both from a technological and biological point of view-to make the hope of precision medicine accessible to all.
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