Biology subjects

Andreopoulou, E.

Publications and source records attributed to Andreopoulou, E..

3 recordsLinked to original sources

bioRxiv2026

A tumor metabolism-angiogenesis-immune axis governs immunotherapy responses

Despite the clinical success of immunotherapy, long-lasting benefit remains restricted to a subset of patients. Tumor metabolic adaptation is emerging as a key factor limiting immunotherapy efficacy. We previously found that glycolysis-low tumor variants, compared to the parental glycolytic tumors, better respond to neoadjuvant CTLA-4 immune checkpoint blockade (ICB) therapy. Here, we investigated new rational modalities to restore immune sensitivity of glycolytic tumors by studying how lowering the tumor-cell glycolytic capacity reshapes the tumor microenvironment (TME) to favor long-lasting systemic anti-tumor responses upon immunotherapy. We found that lowering glycolysis in cancer cells through LDHA-knock down (KD) results in TME displaying normalized vasculature, reduced angiogenic markers, increased high endothelial venules (HEVs), and enhanced recirculation of CD8+ T cells both in and out of the tumor. By leveraging public transcriptomic data sets from human solid cancers, we confirmed that glycolysis positively correlates with neo-angiogenesis and inversely correlates with features of vascular normalization and immune cytolytic activity. Moreover, a tumor signature that incorporates glycolysis- and angiogenesis-related genes as positive features, and normal vasculature, HEV, and immune cytolytic activity genes as negative features predicted poor outcomes better than the individual features across most human solid tumor types in the TCGA. To determine the therapeutic implication of these interrelated processes, we asked if targeting the vasculature would restore immunotherapy responses in glycolytic tumors. We found that combining low-dose anti-VEGFR2 with CTLA-4 blockade induces tumor regressions and protection from metastases in glycolytic tumors. These therapeutic effects were associated with vasculature normalization and increased abundance of HEVs and concentrations of lymphangiogenic factors in the TME of glycolytic tumors. Moreover, anti-VEGFR2 with anti-CTLA-4 restored recirculation of anti-tumor CD8+ T cells in and out of the TME in glycolytic tumors, with specific increases in intratumoral recruitment and activation of cytolytic CD62LCD44CD8 T cells expressing VEGFR2 and low levels of CTLA-4, suggesting potential novel direct synergistic effects of anti-VEGFR2 and anti-CTLA-4 on CD8+ T cells. Conversely, this combination opposed the beneficial immune and vascular TME features of LDHA-KD tumors, indicating tumor-metabolic-dependent effects. Accordingly, we found that standard combined regimens of anti-VEGF and ICB therapy improve survival with respect to ICB alone in patients with glycolysis-high but not glycolysis-low tumors. Together, these findings indicate that tumor cell glycolysis "primes" the TME for aberrant vascular architecture and T-cell exclusion, and that modulating the tumor vasculature can unravel these mechanisms restoring immune responsiveness. This suggests that tailoring anti-angiogenic and immunotherapy combinations to the tumor glycolytic state and associated vasculature profiles may restore immune surveillance and overcome therapy resistance.

immunology↗

bioRxiv2020

Unacylated ghrelin and AZP531 suppress the 3D growth of breast cancers

Breast cancer is the most common type of cancer in women and notwithstanding important therapeutic advances, it remains the second leading cause of cancer-related death in the US. Despite extensive research relating to the hormone ghrelin, responsible for the stimulation of growth hormone release and appetite, little is known of the effects of its unacylated form, especially in cancer. One major area of research relates to its reported effects to increase insulin sensitivity in diabetics, this being the basis for the development of unacylated ghrelin analog, AZP531 or livoletide, now in clinical trials for the treatment of Prader-Willi Syndrome. The mechanism of action of unacylated ghrelin is largely uncharacterized, in any system, because it does not bind to or activate the cognate ghrelin receptor, GHSR1a. The present study aimed to characterize effects of unacylated ghrelin on breast cancer cells, define its mechanism of action, and explore the therapeutic potential of unacylated ghrelin or analog AZP531. We report potent effects of unacylated ghrelin, at picomolar doses, on the growth of breast cancer cells, dependent on 3D culture and activation of Gi. Suppression of MAPK signaling by unacylated ghrelin leads to cell cycle arrest and apoptosis. AZP531 also suppresses the growth of breast cancer cells in vitro and in xenografts, and may be a novel approach for the safe and effective treatment of breast cancer.

cancer biology↗

bioRxiv2019

In silico screening of GMQ-like compounds reveals guanabenz and sephin1 as new allosteric modulators of acid-sensing ion channel 3

Acid-sensing ion channels (ASICs) are voltage-independent cation channels that detect decreases in extracellular pH. Dysregulation of ASICs underpins a number of pathologies. Of particular interest is ASIC3, which is recognised as a key sensor of acid-induced pain and is instrumental in the establishment of pain arising from inflammatory conditions, such as rheumatoid arthritis. Thus, the identification of new ASIC3 modulators and the mechanistic understanding of how these compounds modulate ASIC3 could be important for the development of new strategies to counteract the detrimental effects of dysregulated ASIC3 activity in inflammation. Here, we report the identification of novel ASIC3 modulators based on the ASIC3 agonist, 2-guanidine-4-methylquinazoline (GMQ). Through a GMQ-guided in silico screening of Food and Drug administration (FDA)-approved drugs, 5 compounds were selected and tested for their modulation of rat ASIC3 (rASIC3) using whole-cell patch-clamp electrophysiology. Of the chosen drugs, guanabenz (GBZ), an 2-adrenoceptor agonist, produced similar effects to GMQ on rASIC3, activating the channel at physiological pH (pH 7.4) and potentiating its response to mild acidic (pH 7) stimuli. Sephin1, a GBZ derivative that lacks 2-adrenoceptor activity, has been proposed to act as a selective inhibitor of a regulatory subunit of the stress-induced protein phosphatase 1 (PPP1R15A) with promising therapeutic potential for the treatment of multiple sclerosis. However, we found that like GBZ, sephin1 activates rASIC3 at pH 7.4 and potentiates its response to acidic stimulation (pH 7), i.e. sephin1 is a novel modulator of rASIC3. Furthermore, docking experiments showed that, like GMQ, GBZ and sephin1 likely interact with the nonproton ligand sensor domain of rASIC3. Overall, these data demonstrate the utility of computational analysis for identifying novel ASIC3 modulators, which can be validated with electrophysiological analysis and may lead to the development of better compounds for targeting ASIC3 in the treatment of inflammatory conditions.

pharmacology and toxicology↗