Biology subjects

Surve, C. R.

Publications and source records attributed to Surve, C. R..

3 recordsLinked to original sources

bioRxiv2026

Tie2 signaling in the tumor microenvironment orchestrates breast cancer cell dissemination through TMEM doorways

During breast cancer metastasis, tumor cells migrate toward intratumoral blood vessels and intravasate through stable structures known as TMEM (Tumor Microenvironment of Metastasis) doorways. TMEM doorways, composed of a Mena-expressing tumor cell, a Tie2hi/VEGFhi macrophage, and an endothelial cell, are clinically validated prognostic markers of distant metastasis in breast cancer and represent the exclusive sites of tumor cell intravasation. We previously demonstrated that Tie2 signaling is essential for TMEM doorway function and tumor cell intravasation. In this study, we investigated how Tie2 signaling promotes tumor cell intravasation and metastasis. Because all three TMEM doorway-associated cell types can express Tie2, we sought to determine which of these cells contribute to the Tie2 signaling-dependent vascular opening at TMEM doorways and tumor cell dissemination. We found that endothelial cells associated with TMEM doorways secrete Ang2, which stimulates VEGF-A expression in Tie2hi macrophages. Elevated VEGF-A levels at TMEM doorways increase vascular permeability, facilitating tumor cell entry into the bloodstream. Using tissue staining and line-scan analysis of Tie2 and lineage markers in human and mouse breast cancer models, we observed Tie2 expression in macrophages, tumor cells, and endothelial cells. To assess functional contributions, we selectively disrupted Tie2 in macrophages, endothelial cells, and cancer cells using CRISPR-Cas9 and RNAi approaches and tested in which of these cell-knockouts of Tie2 expression affected transendothelial migration in vitro. Macrophage-specific Tie2 deletion had the greatest impact on tumor cell intravasation. To confirm this finding in vivo, we generated a mouse model with inducible, macrophage-specific Tie2 knockout. Acute, targeted loss of Tie2 specifically in macrophages significantly reduced TMEM doorway associated vascular opening and tumor cell intravasation. Together, these findings establish macrophage Tie2 signaling as a critical driver of TMEM doorway-mediated vascular permeability and metastatic dissemination in breast cancer.

cancer biology↗

bioRxiv2024

Signaling events at TMEM doorways provide potential targets for inhibiting breast cancer dissemination

Tumor cell intravasation is essential for metastatic dissemination, but its exact mechanism is incompletely understood. We have previously shown that in breast cancer, the direct and stable association of a tumor cell expressing Mena, a Tie2hi/VEGFhi macrophage, and a vascular endothelial cell, creates an intravasation portal, called a "tumor microenvironment of metastasis" (TMEM) doorway, for tumor cell intravasation, leading to dissemination to distant sites. The density of TMEM doorways, also called TMEM doorway score, is a clinically validated prognostic marker of distant metastasis in breast cancer patients. Although we know that tumor cells utilize TMEM doorway-associated transient vascular openings to intravasate, the precise signaling mechanisms involved in TMEM doorway function are only partially understood. Using two mouse models of breast cancer and an in vitro assay of intravasation, we report that CSF-1 secreted by the TMEM doorway tumor cell stimulates local secretion of VEGF-A from the Tie2hi TMEM doorway macrophage, leading to the dissociation of endothelial junctions between TMEM doorway associated endothelial cells, supporting tumor cell intravasation. Acute blockade of CSF-1R signaling decreases macrophage VEGF-A secretion as well as TMEM doorway-associated vascular opening, tumor cell trans-endothelial migration, and dissemination. These new insights into signaling events regulating TMEM doorway function should be explored further as treatment strategies for metastatic disease.

cancer biology↗

bioRxiv2020

Live imaging of breast tumors shows macrophage-dependent induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination

Cancer stem cells (CSCs) play an important role during metastasis, but the dynamic behavior and induction mechanisms of CSCs are not well understood. We employed high-resolution intravital microscopy using a CSC biosensor to directly observe CSCs in live mice with mammary tumors. CSCs display the slow-migratory, invadopod-rich phenotype that is the hallmark of disseminating tumor cells. CSCs are enriched near macrophages, particularly near macrophage-containing intravasation sites called Tumor Microenvironment of Metastasis (TMEM) doorways. A dramatic enrichment of CSCs occurs on association with TMEM doorways, contributing to the finding that CSCs represent [~]>60% of circulating tumor cells. Mechanistically, stemness is induced in non-stem cancer cells upon their direct contact with macrophages via Notch signaling. In breast cancers from patients, the density of TMEM doorways correlates strongly with the proportion of cancer cells expressing stem cell markers, indicating that in human breast cancer TMEM doorways are not only cancer cell intravasation portals but also CSC programming sites. One Sentence SummaryIntravital imaging reveals macrophage-mediated induction of cancer stem cells in vivo and their dramatic enrichment on dissemination through TMEM doorways.

cancer biology↗