Biology subjects

Oktay, M.

Publications and source records attributed to Oktay, M..

3 recordsLinked to original sources

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↗

bioRxiv2023

FAK family proteins regulate in vivo breast cancer metastasis via distinct mechanisms.

Breast cancer is the most commonly diagnosed malignancy and the major leading cause of tumor-related deaths in women. It is estimated that the majority of breast tumor-related deaths are a consequence of metastasis, to which no cure exists at present. The FAK family proteins Proline-rich tyrosine kinase (PYK2) and focal adhesion kinase (FAK) are highly expressed in breast cancer, but the exact cellular and signaling mechanisms by which they regulate in vivo tumor cell invasiveness and consequent metastatic dissemination are mostly unknown. Using a PYK2 and FAK knockdown xenograft model we show here, for the first time, that ablation of either PYK2 or FAK decreases primary tumor size and significantly reduces Tumor MicroEnvironment of Metastasis (TMEM) doorway activation, leading to decreased intravasation and reduced spontaneous lung metastasis. Intravital imaging analysis further demonstrates that PYK2, but not FAK, regulates a motility phenotype switch between focal adhesion-mediated fast motility and invadopodia-dependent, ECM-degradation associated slow motility within the primary tumor. Furthermore, we validate our in vivo and intravital imaging results with integrated transcriptomic and proteomic data analysis from xenograft knockdown tumors and reveal new and distinct pathways by which these two homologous kinases regulate breast tumor cell invasiveness and consequent metastatic dissemination. Our findings identify PYK2 and FAK as novel mediators of mammary tumor progression and metastasis and as candidate therapeutic targets for breast cancer metastasis.

cancer biology↗

bioRxiv2021

Primary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells.

Metastases are initiated by disseminated tumor cells (DTCs) that depart from the primary tumor and colonize target organs. Growing evidence suggests that the microenvironment of the primary tumor lesion primes DTCs to display dormant or proliferative fates in target organs. However, the manner in which events taking place in the primary tumor influence DTC fate, sometimes long after dissemination, remains poorly understood. With the advent of a novel intravital imaging technique called the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we have, for the first time, been able to study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find, across several models, a high rate of success for tumor cells to complete the initial steps of the metastatic cascade in the secondary site, including retention of DTCs in the lung vasculature, speed of extravasation, and survival after extravasation. Importantly, initiation of metastatic growth was controlled primarily by a rate-limiting step that occurred post-extravasation and at the stage of the conversion of single DTCs from a dormant to a proliferative state. Detailed analysis of these events revealed that, even before dissemination, a subset of macrophages within the primary tumor induces, in tumor cells that are about to disseminate, the expression of proteins that regulate a pro- dissemination (MenaINV) and pro-dormancy (NR2F1) phenotype. Surprisingly, if cancer cells are intravenously injected, the rate limiting stages of MenaINV-associated extravasation, dormancy, and other parameters, are lost or altered in a way that impacts how DTCs progress through the metastatic cascade. Our work provides novel insight into how specific primary tumor microenvironments prime a subpopulation of cells for dissemination and dormancy. We also propose that dissecting mechanisms of metastasis, or testing anti-metastatic therapies, may yield results of limited application if derived from models that do not follow spontaneous dissemination. SIGNIFICANCEThis study provides important insight into the contribution of primary tumor microenvironmental niches to cancer metastasis by identifying the manner in which these niches spawn subpopulations of DTCs that are primed for dissemination and dormancy in the secondary site. This study may provide novel targets that could be inhibited to prevent successful colonization of the secondary site and, hence, metastasis.

cancer biology↗