Biology subjects

Vlashi, E.

Publications and source records attributed to Vlashi, E..

3 recordsLinked to original sources

bioRxiv2025

Inhibition of AXL dependent non-professional efferocytosis sensitizes pancreatic cancer to immune checkpoint blockade

AXL, a receptor tyrosine kinase, is upregulated in the majority of pancreatic adenocarcinoma (PDAC) and is associated with aggressive tumor behavior. Canonically, AXL is essential for efferocytosis, or the immunologically silent phagocytic clearance of apoptotic cells. While crucial to ensure self-tolerance, efferocytosis in cancer removes tumor antigens and dampens the antitumor response to create a pro-tumorigenic environment. Here, we show that PDAC cells co-opt the AXL pathway to act as non-professional efferocytes and clear chemotherapy induced apoptotic cells from their environment in vitro and in vivo. Inhibition of AXL with the selective inhibitor BGB324 inhibits efferocytosis and increases apoptotic cell burden, immunogenic cell death, and CD8 T cell infiltration in gemcitabine treated tumors in vivo. Single cell RNA expression analysis reveal that AXL inhibited gemcitabine treated tumors are enriched in the immunecheckpoint responsive TCF1+ CD8 T cells and respond to anti-PD1 therapy in vivo. We establish a novel ability of pancreatic cancer cells to engage in non-professional efferocytosis in response to chemotherapy. Inhibiting this response can be leveraged to sensitize this classically immune quiescent cancer to immunotherapy.

cancer biology↗

bioRxiv2022

NADPH oxidase promotes glioblastoma radiation resistance in a PTEN-dependent manner

AimsThe goal of this study was to determine whether NADPH oxidase (NOX)-produced reactive oxygen species enhances brain tumor growth of glioblastoma (GBM) under hypoxic conditions and during radiation treatment. ResultsExogenous ROS promoted brain tumor growth in gliomasphere cultures that expressed functional PTEN, but not in tumors that were PTEN deficient. Hypoxia induced the production of endogenous cytoplasmic ROS and tumor cell growth via activation of NOX. NOX activation resulted in oxidation of PTEN and downstream Akt activation. Radiation also promoted ROS production via NOX which, in turn, resulted in cellular protection that could be abrogated by knockdown of the key NOX component, p22. Knockdown of p22 also inhibited tumor growth and enhanced the efficacy of radiation in PTEN-expressing GBM cells. InnovationWhile other studies have implicated NOX function in GBM models, these studies demonstrate NOX activation and function under physiological hypoxia and following radiation in GBM, two conditions that are seen in patients. NOX plays an important role in a PTEN-expressing GBM model system, but not in PTEN-non-functional systems and provide a potential, patient-specific therapeutic opportunity. ConclusionsThis study provides a strong basis for pursuing NOX inhibition in PTEN-expressing GBM cells as a possible adjunct to radiation therapy.

cancer biology↗

bioRxiv2019

The Dopamine Receptor Antagonist TFP Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma

Glioblastoma (GBM) is the deadliest adult brain cancer and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 months over surgery alone but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP caused loss of radiation-induced Nanog mRNA expression, activation of GSK3 with consecutive post-translational reduction in p-Akt, Sox2 and {beta}-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment resistant, induced GICs. SignificanceGBM is the most common and most deadly adult brain cancer. The current standard-of-care is surgery followed by RT and temozolomide, which results in a median survival time of only 15 months. The efficacy of chemotherapies and targeted therapies in GBM is very limited because most of these drugs do not pass the blood-brain-barrier. Ultimately, all patients succumb to the disease. Our study describes radiation-induced cellular plasticity as a novel resistance mechanism in GBM. We identified a dopamine receptor antagonist as a readily available, FDA-approved drug known to penetrate the blood-brain-barrier which prevents phenotype conversion of glioma cells into glioma-initiating cells and prologs survival in mouse models of GBM, thus suggesting that it will improve the efficacy of RT without increasing toxicity.

neuroscience↗