Biology subjects

Gil-Henn, H.

Publications and source records attributed to Gil-Henn, H..

7 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↗

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

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↗

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↗

bioRxiv2022

A novel Pyk2-derived peptide inhibits invadopodia-mediated breast cancer metastasis

The non-receptor tyrosine kinase Pyk2 is highly expressed in breast cancer, where it mediates invadopodia formation and function via interaction with the actin-nucleation promoting factor cortactin. Here, we designed a cell-permeable peptide inhibitor that contains the second proline-rich region (PRR2) sequence of Pyk2, which binds to the SH3 domain of cortactin and blocks spontaneous lung metastasis in immune-competent mice by inhibiting invadopodia maturation and function. The native structure of the Pyk2-PRR2:cortactin-SH3 complex was determined using nuclear magnetic resonance (NMR), revealing an extended class II interaction surface spanning the canonical binding groove and a second hydrophobic surface which significantly contributes to ligand affinity. Using structure-guided design, we created a mutant peptide lacking critical residues involved in binding that failed to inhibit invadopodia maturation and function and consequent metastatic dissemination in mice. Our findings shed light on the specific molecular interactions between Pyk2 and cortactin and suggest that their inhibition may be used as a novel strategy for blocking breast cancer metastasis.

cancer biology↗

bioRxiv2018

L-Norvaline, a New Therapeutic Agent against Alzheimer s disease.

Alzheimers disease (AD) is a slowly progressive neurodegenerative disorder with an insidious onset. The disease is characterized by cognitive impairment and a distinct pathology with neuritic plaques and neurofibrillary tangles.\n\nGrowing evidence highlights the role of arginase activity in the manifestation of AD. Upregulation of arginase was shown to contribute to endothelial dysfunction, atherosclerosis, diabetes, and neurodegeneration. Regulation of arginase activity appears to be a promising approach for interfering with the pathogenesis of AD and other metabolic disorders. Therefore, the enzyme represents a novel therapeutic target.\n\nHere, we administer an arginase inhibitor L-norvaline to a mouse model of AD. Then, we evaluate the neuroprotective effect of L-norvaline using immunohistochemistry, proteomics, and quantitative polymerase chain reaction assays. Finally, we identify the biological pathways activated by the treatment.\n\nRemarkably, we find that L-norvaline treatment reverses the cognitive decline in AD mice. We show the treatment is neuroprotective as indicated by reduced beta-amyloidosis, alleviated microgliosis, and TNF transcription levels. Moreover, elevated levels of neuroplasticity related protein PSD-95 were detected in the hippocampi of mice treated with L-norvaline. Furthermore, we disclose several biological pathways, which are involved in cell survival and neuroplasticity and are activated by the treatment.\n\nThrough these modes of action, L-norvaline has the potential to improve the symptoms of AD and even interfere with its pathogenesis. As such, L-norvaline is a promising neuroprotective molecule that might be tailored for the treatment of a range of neurodegenerative disorders.

neuroscience↗

bioRxiv2018

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

The urea cycle plays a role in the pathogenesis of Alzheimers disease (AD). Arginase-I accumulation at sites of amyloid-beta deposition is associated with L-arginine deprivation and neurodegeneration. Moreover, a positive interaction between the arginase-II and mTOR-S6K1 pathways promote inflammation and oxidative stress. In this study, we treated 3xTg-AD mice exhibiting increased ribosomal protein S6 kinase beta-1 (S6K1) activity and wild-type (WT) mice with L-norvaline. The substance combines unique properties of arginase and S6K1 inhibition. The treated 3xTg-AD mice demonstrated significantly improved acquisition of spatial memory, associated with a substantial reduction of microgliosis and shift from activated to resting phenotype. Moreover, an increase of dendritic spines density and escalation of the expression rates of neuroplasticity related proteins were followed by a decline in the levels of amyloid-beta toxic oligomeric and fibrillar species in the hippocampus. Our findings associate local amyloid-beta-driven and immune-mediated response with altered L-arginine metabolism and suggest that arginase and S6K1 inhibition by L-norvaline can delay progression of AD.

neuroscience↗