Nanostring analysis of Extracellular vesicles and other particles in lung cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE303318 | GEO | 2026/07/15
REPOSITORIES: GEO
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Project description:Lung cancer is the deadliest cancer worldwide, primarily due to metastatic spread. Tumor-derived extracellular vesicles (EVs) play a crucial role in the formation of pre-metastatic niches (pMNs), facilitating the spread and expansion of circulating cancer cells. So far, little is known about the role of plasma EVs in lung cancer pMN formation. We aim to elucidate the EV role in pMN formation and identify new prognostic biomarkers for early-stage lung cancer.Plasma-derived EVs were obtained by ultracentrifugation from early-stage lung cancer patients who survived at 5 years (ESA-EVs) and patients who died within two years (ESD-EVs). Heavy-smokers cancer free individuals were used as control (HS-EVs). Functional in vitro experiments on endothelial cells were carried out using 15ug of EVs from different groups for 48h. We observed that ESD-EVs significantly induced a “pro-inflammatory” endothelial phenotype. Characterization of ESD-EV revealed higher levels of miR-29 and C4a compared to ESA and HS-EVs. Concomitant miR-29 transfection and C4a administration in endothelial cells recapitulated the pro-inflammatory activation observed with EVs. In conclusion, we showed that plasma EVs could drive lung pMN formation, conferring a pro-inflammatory phenotype to endothelial cells to favour metastasis outgrowth
2026-07-15 | GSE302138 | GEO
Project description:Tumor-derived extracellular vesicles (EVs) play critical roles in premetastatic niche (PMN) formation. Here, we demonstrated that EVs from highly metastatic osteosarcoma cell lines preferentially localized to lung fibroblasts and induce inflammatory PMN formation. High-throughput profiling of EVs-derived long noncoding RNAs (lncRNAs) identified lncOSLMT as a candidate enriched in EVs and markedly upregulated in patient tumor and serum, with elevated levels correlating with poor prognosis. Mechanistically, in EVs, lncOSLMT directly bound the RNA-binding protein hnRNPA2B1. Following internalization by recipient lung fibroblasts, hnRNPA2B1 bound to N⁶-methyladenosine (m⁶A) -modified sites in the 3’UTR of PTGS2 mRNA, leading to transcript stabilization and increased COX-2 expression. For therapeutic intervention, we developed lactoferrin-resveratrol (LF-RES) nanoparticles, which loaded siRNA against lncOSLMT. Intravenous administration of LF-RES-siRNA in mice reduced EVs-induced lung inflammation and suppressed lung metastasis. Combination with EP2/EP4 antagonists produced enhanced anti-metastatic effects. These findings establish EVs-derived lncOSLMT as a key regulator of inflammatory PMN formation in the lung and highlight the potential of LF-RES-siRNA nanoparticles as a targeted anti-metastatic therapy in osteosarcoma.
2026-01-04 | GSE308154 | GEO
Project description:Tumor-derived extracellular vesicles (EVs) play critical roles in premetastatic niche (PMN) formation. Here, we demonstrated that EVs from highly metastatic osteosarcoma cell lines preferentially localized to lung fibroblasts and induce inflammatory PMN formation. High-throughput profiling of EVs-derived long noncoding RNAs (lncRNAs) identified lncOSLMT as a candidate enriched in EVs and markedly upregulated in patient tumor and serum, with elevated levels correlating with poor prognosis. Mechanistically, in EVs, lncOSLMT directly bound the RNA-binding protein hnRNPA2B1. Following internalization by recipient lung fibroblasts, hnRNPA2B1 bound to N⁶-methyladenosine (m⁶A) -modified sites in the 3’UTR of PTGS2 mRNA, leading to transcript stabilization and increased COX-2 expression. For therapeutic intervention, we developed lactoferrin-resveratrol (LF-RES) nanoparticles, which loaded siRNA against lncOSLMT. Intravenous administration of LF-RES-siRNA in mice reduced EVs-induced lung inflammation and suppressed lung metastasis. Combination with EP2/EP4 antagonists produced enhanced anti-metastatic effects. These findings establish EVs-derived lncOSLMT as a key regulator of inflammatory PMN formation in the lung and highlight the potential of LF-RES-siRNA nanoparticles as a targeted anti-metastatic therapy in osteosarcoma.
2026-01-04 | GSE308128 | GEO
Project description:Tumor-derived extracellular vesicles (EVs) play critical roles in premetastatic niche (PMN) formation. Here, we demonstrated that EVs from highly metastatic osteosarcoma cell lines preferentially localized to lung fibroblasts and induce inflammatory PMN formation. High-throughput profiling of EVs-derived long noncoding RNAs (lncRNAs) identified lncOSLMT as a candidate enriched in EVs and markedly upregulated in patient tumor and serum, with elevated levels correlating with poor prognosis. Mechanistically, in EVs, lncOSLMT directly bound the RNA-binding protein hnRNPA2B1. Following internalization by recipient lung fibroblasts, hnRNPA2B1 bound to N⁶-methyladenosine (m⁶A) -modified sites in the 3’UTR of PTGS2 mRNA, leading to transcript stabilization and increased COX-2 expression. For therapeutic intervention, we developed lactoferrin-resveratrol (LF-RES) nanoparticles, which loaded siRNA against lncOSLMT. Intravenous administration of LF-RES-siRNA in mice reduced EVs-induced lung inflammation and suppressed lung metastasis. Combination with EP2/EP4 antagonists produced enhanced anti-metastatic effects. These findings establish EVs-derived lncOSLMT as a key regulator of inflammatory PMN formation in the lung and highlight the potential of LF-RES-siRNA nanoparticles as a targeted anti-metastatic therapy in osteosarcoma.
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Project description:Pancreatic cancer is associated with a high rate of metastasis and poor prognosis. The formation of a premetastatic niche (PMN) facilitates cancer cell spread and contributes to cancer mortality. Using murine pancreatic cancer models based on expression of oncogenic KRAS in the pancreas epithelium, we discovered that remodeling of the lung microenvironment occurred in mice bearing pancreatic precursor lesions prior to cancer formation. This early lesion premetastatic niche (EL-PMN) resembled the PMN in cancer-bearing mice, and both feature characteristics of overt metastasis, such as transcriptional reprogramming, activation of fibroblast STAT3 signaling, and infiltration of immunosuppressive ARG1+ macrophages. Both pancreatic cancer patients and mouse models demonstrated elevated serum IL6. Inactivating oncogenic KRAS reduced serum IL6 and reverted fibroblast STAT3 phosphorylation in mouse lungs; loss of lung fibroblast STAT3 phosphorylation was similarly observed when mice were treated with the pan-RAS inhibitor RMC7977. While ARG1+ macrophage infiltration was dispensable for fibroblast STAT3 activation, IL6 blockade inhibited lung fibroblast STAT3 activation. Functionally, fibroblast STAT3 activation was necessary for lung metastasis establishment and growth. Interestingly, activation of STAT3 in the PMN was present in the lungs but not in the liver, where fibroblast reprogramming occurred only in overt metastasis, pointing to organ-specific PMN formation. In human metastasis samples, phosphorylated STAT3 in fibroblasts was similarly more abundant in the lungs than liver. Together, these data point to organ-specific mechanisms driving formation of the PMN and indicate that reprogramming of the microenvironment prior to metastasis might support early dissemination of pancreatic cancer.
2025-10-07 | GSE292712 | GEO
Project description:Tissue stiffness is a critical prognostic factor in breast cancer and is associated with metastatic progression. Here we show an alternative and complementary hypothesis of tumor progression whereby physiological matrix stiffness affects the quantity and protein cargo of small EVs produced by cancer cells, which in turn aid cancer cell dissemination. Primary patient breast tissue produces significantly more EVs from stiff tumor tissue than soft tumor adjacent tissue. EVs released by cancer cells on matrices that model human breast tumors (25 kPa; stiff EVs) feature increased adhesion molecule presentation (ITGα2β1, ITGα6β4, ITGα6β1, CD44) compared to EVs from softer normal tissue (0.5 kPa; soft EVs), which facilitates their binding to extracellular matrix (ECM) protein collagen IV, and a 3-fold increase in homing ability to distant organs in mice. In a zebrafish xenograft model, stiff EVs aid cancer cell dissemination. Moreover, normal, resident lung fibroblasts treated with stiff and soft EVs change their gene expression profiles to adopt a cancer associated fibroblast (CAF) phenotype. These findings show that EV quantity, cargo, and function depend heavily on the mechanical properties of the extracellular microenvironment.
2024-06-22 | PXD049019 | Pride
Project description:Pre-metastatic niche (PMN) formation is a critical step in metastatic progression, yet the biological effect of subtherapeutic-dose of ionizing radiation (SDIR) following radiotherapy on this process remains unclear. Using a 4T1 breast cancer mouse model, we investigated the effects of SDIR (3×0.3 Gy) on lung PMN development and metastasis formation. Lung PMNs were exposed to SDIR on days 8–10 post-tumor induction, followed by mastectomy on day 18, and analyzed on day 24. SDIR significantly increased total metastatic volume (TMV) in lungs, suggesting an accelerated PMN formation. Mechanistically, SDIR upregulated Bv8 expression, enhanced neutrophil recruitment, and increased MMP9, S100A8, and IL-6 production in the PMN by day 11, though differences between irradiated and non-irradiated PMN were no longer evident by day 14. Notably, Bv8 inhibition prevented SDIR-induced neutrophil recruitment but did not reduce TMV, indicating additional mechanisms in SDIR-driven metastasis. Proteomic analysis revealed SDIR-induced metabolic reprogramming, extracellular matrix (ECM) remodeling, and upregulation of adhesion-related pathways, driving a microenvironment that accelerates tumor invasion and metastatic outgrowth. By demonstrating that SDIR reprograms the pre-metastatic lung microenvironment, this study highlights the need to integrate organ-specific radiation exposure into predictive models of metastasis and identifies metabolic and immune-stromal pathways as potential targets for therapeutic intervention.
2025-07-21 | PXD062108 | Pride
Project description:Blood coagulation and cancer are intricately related. Hypercoagulation associated with cancer leads to aberrant thrombin generation, which contributes to thrombosis. Thrombin also activates anticoagulant protein C and the activated protein C (aPC), in addition to regulating the coagulation pathway, it also elicits cell signaling by binding to endothelial cell protein C receptor (EPCR) and activating protease-activated receptor 1 (PAR1)-mediated cell signaling. Earlier studies showed that aPC promotes lung adenocarcinoma survival and metastasis. However, the underlying mechanism remains largely unknown. Our present study provides mechanistic insight into how aPC promotes lung adenocarcinoma survival, metastasis, and drug resistance. Our study shows that aPC, through EPCR-PAR1-driven activation of RhoA-ROCKII-JNK1/2-MLC2 signaling, triggers extracellular vesicle (EV) release from lung adenocarcinoma cells. aPC-EVs, via the transfer of microRNA (miR)-200a, promote proliferation, migration, and invasion of normal lung epithelial cells. They also confer resistance to lung cancer against chemotherapeutic agents. Inhibition of miR-200a functions through the incorporation of anti-miR-200a abrogates aPC-EVs-mediated tumorigenic effects. Furthermore, loading miR-200a mimic into control EVs showed similar phenotypic responses to that of aPC-EVs. miR-200a is shown to target SOX17 in the recipient cells, leading to tumorigenesis. miR-200a upregulation and SOX17 downregulation are consistently observed in lung cancer tissues in the UALCAN portal database of clinical specimens. Consistent with these findings, our in vivo studies in BALB/c nude mice showed that aPC-EVs from lung cancer cells promote tumor growth, metastasis, and drug resistance through miR-200a transfer. Targeting EV biogenesis, EV’s miR-200a, and/or EV uptake mechanisms may offer novel therapeutic strategies in limiting lung tumorigenesis, thereby increasing patients’ survival.
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2024-10-18 | GSE277589 | GEO
Project description:Macrophages that acquire an immunosuppressive phenotype are crucial for creating the pre-metastatic niche (PMN), which is essential for facilitating breast cancer metastasis to the distant organ. Our study showed that increased aryl hydrocarbon receptor (AHR) activity in lung macrophages is vital for establishing the immunosuppressive PMN in breast cancer. AHR activation led to higher PD-L1 expression on macrophages through directly binding to the promoter of Pdl1, subsequently, promoting Treg cell differentiation in the PMN. Mice with Ahr conditional deletion in macrophages had reduced lung metastasis of breast cancer. The elevated AHR level in PMN macrophages was induced by GM-CSF released from breast cancer cells, which activated STAT5 and prevented AHR ubiquitination in macrophages. In breast cancer patients, the expression of AHR and PD-L1 correlated with Treg cell infiltration, and high AHR expression was associated with a poor prognosis. Our findings uncover a previously unknown cellular and molecular mechanism through which macrophages establish the lung PMN in breast cancer.
2025-09-30 | GSE277325 | GEO