OBJECTIVE:The dismal prognosis of breast cancer brain metastasis (BCBM) is attributed to a maladapted tumor microenvironment. This study was aimed at deciphering the role of novel intercellular communicators, tumor-derived migrasomes, in driving BCBM progression, with a focus on their ability to co-opt brain-resident microglia. METHODS:Migrasomes were isolated and characterized from brain-tropic (231-BR; Mig-BCBM) and parental breast cancer cells, patient-derived metastatic breast cancer tissues, and mice BCBM tissues. The functional axis was delineated through an integrative approach encompassing proteomics, in vitro co-culture systems, in vivo brain colonization assays, genetic perturbations, and a pharmacological intervention with the clinical-stage TGFβR1 inhibitor galunisertib. RESULTS:Mig-BCBM were internalized by microglia, thus triggering their repolarization to a pro-tumorigenic, M2-like state, both in vitro and in vivo. Proteomic profiling identified integrin β3 (ITGβ3) as a key regulator selectively packaged into Mig-BCBM. Mechanistically, migrasomal ITGβ3 activated the PI3K/AKT pathway in microglia, thus driving M2 polarization. These reprogrammed microglia secreted high levels of TGFβ1, which in turn fostered a metastatic niche by inducing Smad2/3-dependent epithelial-mesenchymal transition (EMT) in tumor cells. Crucially, we uncovered a self-amplifying feedforward loop in which microglial-derived TGFβ1 transcriptionally upregulates TSPAN4 via EGR1 in cancer cells, thus enhancing migrasome biogenesis and subsequent ITGβ3 loading. Disrupting this loop with galunisertib potently inhibited BCBM outgrowth and colonization in vivo, without systemic toxicity. CONCLUSIONS:This study identified a targetable circuit in BCBM wherein tumor-derived migrasomes, via ITGβ3, engage microglia in a TGFβ1-centered crosstalk. Because this self-reinforcing ITGβ3-TGFβ1 axis sustains the pro-metastatic niche, its disruption might provide a rational therapeutic strategy.
Objective Intratumoral heterogeneity refers to the presence of distinct subpopulations of cancer cells within a single tumor, which exhibits variations in phenotypic traits, such as proliferation rate, drug sensitivity, and metastatic potential. Dynamic interactions among heterogeneous cell populations have a critical role in tumor progression. Increasing evidence underscores the importance of intercellular communication among heterogeneous cancer cell subpopulations in driving malignancy. However, the molecular mechanisms governing such cancer cell-to-cancer cell interactions are poorly understood. Methods Exosomes were isolated from highly metastatic breast cancer cells (HM-BCCs) and low metastatic breast cancer cells (LM-BCCs). The role of exosome-mediated intercellular communication on metastatic behavior was assessed using wound healing and Transwell assays. Gene knockdown and overexpression strategies, small-molecule inhibitors, and xenograft mouse models were used to elucidate the role of exosomal EPHA2. Results Exosomes derived from HM-BCCs considerably enhanced the migratory and invasive capabilities of LM-BCCs in vitro and increased the metastatic potential in vivo. Mechanistically, EPHA2 was identified as a key protein enriched in exosomes from HM-BCCs and was shown to be transferred to LM-BCCs by these vesicles. Exosomal EPHA2 promoted epithelial-to-mesenchymal transition in LM-BCCs when internalized by stabilizing TGF-u03B2RI and activating the transforming growth factor-u03B2/mothers against decapentaplegic homolog 3 (TGF-u03B2/SMAD3) signaling pathway, thereby facilitating the acquisition of a metastatic phenotype. Conclusions The results underscore the pivotal function of exosomal EPHA2 in mediating the transfer of metastatic potential among heterogeneous breast cancer cell populations. Targeting the EPHA2-TGF-u03B2RI signaling axis may provide a novel therapeutic approach for preventing or limiting breast cancer metastasis.
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central sensor of innate immunity that plays critical roles in recognizing cytosolic DNA and initiating antitumor immune responses. However, this pathway exhibits extensive spatiotemporal duality and context dependency in tumor regulation. In recent years, modulating this pathway to convert immunologically "cold" tumors into immunologically "hot," inflamed tumors has emerged as a cutting-edge strategy to reverse resistance to immune checkpoint inhibitors (ICIs). This review outlines the molecular mechanisms underlying the activation and regulation of the cGAS-STING pathway, with emphasis on its complex role in orchestrating the tumor immune phenotypic switch. A nuanced analysis of the pathway's duality distinguishes between acute immunostimulatory activation and chronic, pro-tumorigenic inflammation driven by chromosomal instability (CIN). Furthermore, current evidence regarding direct and indirect T-cell modulation, as well as pathway-mediated remodeling of the tumor microenvironment (TME) across diverse malignancies, is discussed in detail. Crucially, the current bottlenecks in clinical translation are described, including evaluation of the failure of first-generation agonists and the promise of next-generation delivery platforms such as antibody-drug conjugates (ADCs) and nanoparticle systems. Finally, a novel strategic framework is proposed involving mapping of specific STING-targeted modalities to distinct TME phenotypes, such as immune-desert, immune-excluded, and exhausted-inflamed states. A detailed understanding of the cGAS-STING axis has substantial value in providing theoretical guidance and supporting clinical translation in the development of next-generation combination immunotherapies, as well as broadening the patient population benefiting from clinical interventions.
Ovarian cancer was the eighth most frequently diagnosed cancer among women in 2022. The global age-standardized incidence rate of ovarian cancer decreased from 7.22/100,000 to 6.71/100,000 from 1990 to 2021. However, incidence trends varied across countries. Declining ovarian cancer incidence rates were reported in high-income countries, such as the United States, Austria, the Netherlands, and Norway, while there were increasing incidence rates in Africa and parts of Asia, including Japan and India. The global age-standardized mortality rate of ovarian cancer decreased from 4.73/100,000 to 4.06/100,000 between 1999 and 2021 with varying trends among countries. Moreover, the age-standardized 5-year net ovarian cancer survival rate in most countries remained < 50%. Several specific factors related to ovarian cancer risk have been identified, including reproductive factors, use of oral contraceptives, anti-inflammatory diets, endometriosis, pelvic inflammatory disease, obesity, diabetes, and occupational asbestos exposure. No screening or prevention strategy has been proven effective in downstaging or reducing mortality from ovarian cancer in an average-risk population without a family cancer history or pathogenic variants. Indeed, risk-reducing salpingo-oophorectomy remains the gold standard for lowering the risk of ovarian cancer in high-risk individuals with hereditary mutations. This review provides a comprehensive overview of the epidemiology, risk factors, screening, and prevention of ovarian cancer, aiming to offer a global perspective on public health strategies for addressing the disease.
