Cancer EVP Uptake in Lung Interstitial Macrophages Enhances Vascular Permeability and Metastatic Potential (in vivo)
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ABSTRACT:
PROVIDER: PRJNA1085348 | ENA |
REPOSITORIES: ENA
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Project description:Enhanced vascular permeability in the pre-metastatic niche facilitates tumor cell extravasation and metastasis. Extracellular vesicles and particles (EVPs) are pivotal mediators of cancer progression, including induction of vascular permeability. We identify a novel mechanism whereby melanoma and osteosarcoma EVPs (B16F10 and K7M2) enhance endothelial cell permeability, tumor extravasation and lung metastasis.In contrast, EVPs from breast tumors (4T1 and 67NR) elicited only mild vascular permeability, tumor cell extravasation, and metastasis. EVP induced vascular leakiness is observed within 48h following tumor implantation and as early one hour following direct injection of the B16F10 or K7M2 derived EVPs in non-tumor bearing mice. Rather than acting directly on endothelial cells, EVPs activated interstitial macrophages (IMs) anddepletion of IM with a CSF1R antibody significantly reduced vascular leakiness and metastatic potential.Subsequent activation of JAK/STAT signaling in IMs induces IL-6 secretion which in turn induces endothelial permeability.B16F10 and K7M2 EVPs highly expressed ITGα5 compared to breast tumors, and knock down ofintegrin-α5impairs IM signaling, vascular permeability and metastasis. Furthermore, in patients Il-6 expression is elevated in tumor-adjacent IMs compared to distant tissues. Our findings identify a key role for IMs in mediating tumor type-specific EVP-driven vascular permeability and metastasis, offering promising targets for therapeutic intervention.
2024-06-26 | GSE261138 | GEO
Project description:Enhanced vascular permeability in the pre-metastatic niche facilitates tumor cell extravasation and metastasis. Extracellular vesicles and particles (EVPs) are pivotal mediators of cancer progression, including induction of vascular permeability. We identify a novel mechanism whereby melanoma and osteosarcoma EVPs (B16F10 and K7M2) enhance endothelial cell permeability, tumor extravasation and lung metastasis.In contrast, EVPs from breast tumors (4T1 and 67NR) elicited only mild vascular permeability, tumor cell extravasation, and metastasis. EVP induced vascular leakiness is observed within 48h following tumor implantation and as early one hour following direct injection of the B16F10 or K7M2 derived EVPs in non-tumor bearing mice. Rather than acting directly on endothelial cells, EVPs activated interstitial macrophages (IMs) anddepletion of IM with a CSF1R antibody significantly reduced vascular leakiness and metastatic potential.Subsequent activation of JAK/STAT signaling in IMs induces IL-6 secretion which in turn induces endothelial permeability.B16F10 and K7M2 EVPs highly expressed integrin-α5 compared to breast tumors, and knock down ofITGα5impairs IM signaling, vascular permeability and metastasis. Furthermore, in patients Il-6 expression is elevated in tumor-adjacent IMs compared to distant tissues. Our findings identify a key role for IMs in mediating tumor type-specific EVP-driven vascular permeability and metastasis, offering promising targets for therapeutic intervention.
2024-06-26 | GSE261137 | GEO
Project description:Cancer EVP Uptake in Lung Interstitial Macrophages Enhances Vascular Permeability and Metastatic Potential (in vitro)
| PRJNA1085337 | ENA
Project description:Tumour-derived Extracellular Vesicle and Particle Reprogramming of Interstitial Macrophages in the Lung Pre-Metastatic Niche Enhances Vascular Permeability and Metastatic Potential
| PRJNA1085343 | ENA
Project description:Vascular permeability is frequently associated with inflammation and it is triggered by chemokines and by a cohort of secreted permeability factors, such as VEGF. In contrast, here we showed that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and it is independent of VEGF. Both global and endothelial-specific deletion of PR block physiological vascular permeability in the uterus while misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of genome-wide transcriptional profile of endothelium and ChIP-sequencing revealed that PR induces a NR4A1 (Nur77/TR3) specific transcriptional program that broadly regulates vascular permeability in response to progesterone. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely and venule-specific regulation of vascular barrier function. Silencing NR4A1 blocks PR-mediated permeability responses indicating a direct link between PR and NR4A1. These results reveal a previously unknown function for progesterone receptor on endothelial cell biology with consequences to physiological vascular permeability and implications to the clinical use of progestins and anti-progestins on blood vessel integrity. Examination of PR binding sites in HUVEC cells using ChIP-seq (non-infected-negative control, PR infected followed by ligand treatment-PR+P or vehicle PR)
2014-01-01 | E-GEOD-43786 | biostudies-arrayexpress
Project description:Vascular permeability is frequently associated with inflammation and it is triggered by chemokines and by a cohort of secreted permeability factors, such as VEGF. In contrast, here we showed that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and it is independent of VEGF. Both global and endothelial-specific deletion of PR block physiological vascular permeability in the uterus while misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of genome-wide transcriptional profile of endothelium and ChIP-sequencing revealed that PR induces a NR4A1 (Nur77/TR3) specific transcriptional program that broadly regulates vascular permeability in response to progesterone. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely and venule-specific regulation of vascular barrier function. Silencing NR4A1 blocks PR-mediated permeability responses indicating a direct link between PR and NR4A1. These results reveal a previously unknown function for progesterone receptor on endothelial cell biology with consequences to physiological vascular permeability and implications to the clinical use of progestins and anti-progestins on blood vessel integrity. Examination of PR target genes in human umbilical vein endothelial cells (HUVECs) using RNA-seq (PR infected only -PR only and PR infected followed by ligand treatment-PR+P)
2014-01-01 | E-GEOD-43788 | biostudies-arrayexpress
Project description:Vascular permeability is frequently associated with inflammation and it is triggered by chemokines and by a cohort of secreted permeability factors, such as VEGF. In contrast, here we showed that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and it is independent of VEGF. Both global and endothelial-specific deletion of PR block physiological vascular permeability in the uterus while misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of genome-wide transcriptional profile of endothelium and ChIP-sequencing revealed that PR induces a NR4A1 (Nur77/TR3) specific transcriptional program that broadly regulates vascular permeability in response to progesterone. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely and venule-specific regulation of vascular barrier function. Silencing NR4A1 blocks PR-mediated permeability responses indicating a direct link between PR and NR4A1. These results reveal a previously unknown function for progesterone receptor on endothelial cell biology with consequences to physiological vascular permeability and implications to the clinical use of progestins and anti-progestins on blood vessel integrity.
2014-01-01 | GSE43788 | GEO
Project description:Vascular permeability is frequently associated with inflammation and it is triggered by chemokines and by a cohort of secreted permeability factors, such as VEGF. In contrast, here we showed that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and it is independent of VEGF. Both global and endothelial-specific deletion of PR block physiological vascular permeability in the uterus while misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of genome-wide transcriptional profile of endothelium and ChIP-sequencing revealed that PR induces a NR4A1 (Nur77/TR3) specific transcriptional program that broadly regulates vascular permeability in response to progesterone. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely and venule-specific regulation of vascular barrier function. Silencing NR4A1 blocks PR-mediated permeability responses indicating a direct link between PR and NR4A1. These results reveal a previously unknown function for progesterone receptor on endothelial cell biology with consequences to physiological vascular permeability and implications to the clinical use of progestins and anti-progestins on blood vessel integrity.
2014-01-01 | GSE43786 | GEO
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