Puerta-Martinez, F. | Search bioRxiv

bioRxiv2025

TMEM Doorway Mediated Metastasis in Pancreatic Ductal Adenocarcinoma by Tie2 Signaling

Pancreatic ductal adenocarcinoma (PDAC) is almost invariably fatal due to early hematogenous dissemination that occurs before the primary tumor is clinically detectable, yet the cellular mechanism of tumor cell intravasation has remained unknown. Using multiphoton intravital imaging in autochthonous and orthotopic PDAC models, we demonstrate that intravasation occurs at Tumor Microenvironment of Metastasis (TMEM) doorways--tri-cellular structures comprising a MENA-expressing tumor cell, a Tie2 macrophage, and an endothelial cell in direct contact. These structures are abundant in human PDAC, enriched for Tie2 macrophages, and markedly reduced after neoadjuvant chemotherapy. Selective pharmacologic inhibition of Tie2 with rebastinib decreases TMEM-associated transient vascular openings, suppresses circulating and hepatic disseminated tumor cells, and--when combined with perioperative FOLFIRINOX after curative-intent resection--improves median survival in murine PDAC. These findings establish TMEM doorways as a common, druggable mechanism of intravasation across epithelial cancers and identify Tie2 macrophages as a therapeutic target to prevent metastatic seeding in PDAC, a disease with no anti-metastatic therapies. TMEM doorway-mediated intravasation in PDAC supports its role as a common gateway for hematogenous metastasis in carcinoma.

cancer biology↗

bioRxiv2024

CD200 depletion in glioma enhances antitumor immunity and induces tumor rejection

High-grade gliomas are a major health challenge with poor prognosis and high morbidity. Immune-checkpoint inhibitors (ICI) have emerged as promising therapeutic options for several malignancies yet show little efficacy against central nervous system (CNS) tumors. CD200 is a newly recognized immune checkpoint that modulates immune homeostasis. CD200 protein is expressed by a variety of cells, including immune cells and stromal cells, and is overexpressed by many tumors. The shedding of CD200 from tumor cells can create an immunosuppressive environment that dampens anti-tumor immunity by modulating cytolytic activity and cytokine expression both within and outside the tumor microenvironment (TME). While it is well-accepted that CD200 induces a pro-tumorigenic environment through its ability to suppress the immune response, we sought to determine the role of glioma-specific expression of CD200. We show that CD200 is expressed across glioma types, is shed from tumor cells, and increases over time in the serum of patients undergoing immunotherapy. Using CD200 knockout (KO) glioma models, we demonstrated that glioma cell-derived CD200 promotes tumor growth in vivo and in vitro. Notably, CD200 KO gliomas are spontaneously rejected by their host, a process that required a fully functional immune system, including NK and T-cells. Moreover, we report that glioma-derived or brain-injected soluble CD200 contributes to the suppression of antigen-specific CD8 T-cells in the draining lymph nodes (dLNs). Our work provides new mechanistic insights regarding CD200-mediated immunosuppression by gliomas. Statement of significanceWe demonstrate mechanisms of the druggable glioma-derived CD200 checkpoint on tumor growth and immune suppression.

immunology↗