A connectivity signature for glioblastoma
Year: 2022
Type: conference-paper
Abstract: Advancements in prevention, detection and treatment of gliomas over the last 40 years have consistently lagged behind those seen in many other tumour types.The hypoxic nature of glioma adds further complications to therapeutic efficacy, as hypoxia limits efficient drug delivery as well as increasing treatment resistance.Furthermore, it is known that hypoxia induces a metabolic shift in tumours which further contributes to this resistance.Therapies that therefore target both the hypoxic tumour microenvironment and metabolic pathways that sustain growth have significant potential to improve patient prognosis.Of the 53 mammalian SLC25A family members, which transport metabolites across the mitochondrial inner membrane, around 23 lack a defined substrate selectivity.Recent reports have suggested that the previously uncharacterised SLC25A39 member of the family is a putative glutathione transporter.It is therefore of significant importance in the regulation of the mitochondrial anti-oxidant response, and could play an important role in hypoxia.We have shown that SLC25A39 is functionally required to maintain cell proliferation of glioma cell lines and patient tumour cells.Metabolic analysis of these knockout/knockdown models suggest that SLC25A39 activity is required for appropriate function of the mitochondrial metabolic network, and its loss results in significant, wide-ranging metabolic dysfunction that spreads beyond the mitochondria.We have also shown that SLC25A39 expression is rapidly upregulated in response to hypoxia-through a HIF-and oxidative stress-mediated response.Excitingly, loss of SLC25A39 expression led to a sensitisation of hypoxic cells to cisplatin, suggesting that targeting this transporter may be a means of improving therapy efficacy for glioma.These data highlight the importance of identifying unknown metabolic transporters that are important for hypoxic tumour metabolism, thereby exposing a potential way to exploit hypoxic areas in these tumours, subsequently making them more vulnerable to treatment.
Source: WFNOS 2022 Abstract Book
Authors: Tobias Kessler, Ling Hai, Dirk C Hoffmann, Henriette Mandelbaum, Ruifan Xie, Jakob Ito, Erik Jung, Sophie Weil, Philipp Sievers, Varun Venkataramani, Daniel Dominguez Azorin, Kathi Ernst, Denise Reibold, Rainer Will, Mario L Suva, Christel Herold-Mende, Felix Sahm, Frank Winkler, Matthias Schlesner, Wolfgang Wick
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4293204146