Biology subjects

Eddy, R. J.

Publications and source records attributed to Eddy, R. J..

3 recordsLinked to original sources

bioRxiv2026

Mena (ENAH) Promotes KRAS-Driven Tumor Growth and Metastatic Progression in Pancreatic Ductal Adenocarcinoma

Metastatic pancreatic ductal adenocarcinoma (PDAC) remains incurable and is projected to become the second leading cause of cancer-related death by 2030. Despite therapeutic advances, median survival remains under one year. Activating KRAS mutations drive the majority of PDAC and underlie their highly aggressive behavior. Although emerging KRAS inhibitors show promise, resistance limits their clinical efficacy, underscoring the need to identify additional regulators of mutant KRAS signaling. We investigated the role of the actin-regulatory protein Mena (ENAH) in KRASG12D-driven PDAC using novel in vitro and orthotopic in vivo models with Mena overexpression and knockdown. Mena overexpression markedly increased primary tumor growth and spontaneous liver metastasis, whereas Mena knockdown delayed tumor onset and reduced metastatic burden. Mechanistically, Mena depletion significantly decreased AKT and ERK activity downstream of KRAS in a SHIP2-mediated manner, indicating that Mena enhances oncogenic signaling required for PDAC progression. These findings reveal Mena as a critical modulator of KRASG12D-driven pancreatic tumor growth and metastasis. By promoting key survival and proliferation pathways, Mena contributes to the aggressive phenotype characteristic of KRAS-mutant PDAC and represents a promising therapeutic target for patients with both locoregional and metastatic disease.

cancer biology↗

bioRxiv2024

Intratumoral CXCL12 Gradients Contextualize Tumor Cell Invasion, Migration and Immune Suppression in Breast Cancer

Although the CXCL12/CXCR4 pathway has been prior investigated for its prometastatic and immuno- suppressive roles in the tumor microenvironment, evidence on the spatiotemporal regulation of these hallmarks has been lacking. Here, we demonstrate that CXCL12 forms a gradient specifically around cancer cell intravasation doorways, also known as Tumor Microenvironment of Metastasis (TMEM) doorways, thus facilitating the chemotactic translocation of prometastatic tumor cells expressing CXCR4 toward the perivascular TMEM doorways for subsequent entry into peripheral circulation. Fur- thermore, we demonstrate that the CXCL12-rich micro-environment around TMEM doorways may cre- ate immunosuppressive niches, whereby CD8+ T cells, despite being attracted to these regions, often exhibit reduced effector functions, limiting their efficacy. While the CXCL12/CXCR4 pathway can mini- mally influence the overall composition of immune cell populations, it biases the distribution of CD8+ T cells away from TMEM doorways, justifying its prior-established role as immunosuppressive factor for CD8+ T cells. Our research suggests that the complex interactions between CXCL12 and the various tumor and immune cell types contributes not only to the completion of the initial steps of the metastatic cascade, but also offers an immunological "sanctuary" to prometastatic tumor cells homed around TMEM doorways. Overall, our study enhances our current understanding on the mechanisms, via which CXCL12 orchestrates tumor cell behavior and immune dynamics, potentially guiding future thera- peutic strategies to combat breast cancer metastasis and improve anti-tumor immunity.

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↗