Biology subjects

Marcelino, H.

Publications and source records attributed to Marcelino, H..

3 recordsLinked to original sources

bioRxiv2025

Glioblastoma cells taste temozolomide via TAS2R43

Bitter taste receptors (TAS2Rs) have a widespread expression in various extraoral organs where they detect the chemical composition of body fluids and trigger biological responses accordingly. Among the chemicals recognised by TAS2Rs there are natural and synthetic compounds including therapeutic drugs. We have shown that TAS2Rs are expressed in the blood-cerebrospinal fluid barrier where they regulate efflux transporters, thereby controlling the transport of compounds into the cerebrospinal fluid. More recently, we assessed the expression of these receptors in human glioblastoma cells, where 20 out of the 26 human TAS2Rs were identified. In this study, we investigated if temozolomide, the standard chemotherapy for glioblastoma, activates the bitter signalling pathway with impact in its therapeutic efficacy. Notably, we found that blocking the bitter taste signalling pathway significantly reduced the anti-proliferative and pro-apoptotic effects of temozolomide, and identified TAS2R43 as the receptor mediating these effects. We propose that upon ligand binding, TAS2R43 modulates multidrug resistance proteins (MDRs) activity, facilitating temozolomide entrance into glioblastoma cells. These findings underscore the importance of the taste transduction pathway in evaluating the chemical composition of the glioblastoma microenvironment. Furthermore, our data suggest that TAS2R43 could serve as a biomarker for the efficacy of temozolomide and other drugs that are substrates of MDRs.

cancer biology↗

bioRxiv2025

Taste receptors' profiling in glioblastoma

Glioblastoma is the most common and aggressive form of primary brain cancer. Despite significant progress in the development of promising therapeutic agents, cancer-targeting therapies often fail to achieve effective concentrations in the brain, limiting their therapeutic efficacy. As such, a deeper understanding of how glioblastoma tumours interact with their microenvironment and assess the chemical composition therein can reveal novel therapeutic strategies. Recent studies have highlighted the critical role of taste receptors, particularly bitter taste receptors (TAS2Rs) and their ligands in cancer progression and metastasis. Activation of TAS2Rs by both natural and synthetic compounds has been associated with drug resistance, apoptosis, and the proliferation of malignant tumours. The sweet taste receptor TAS1R2/TAS1R3, or the umami receptor TAS1R1/TAS1R3, as recognised sensors of glucose levels and aminoacids, respectively, are also of interest in the context of cancer metabolism. In this study, we investigated the expression and function of TAS2Rs, TAS1R2/TAS1R3 and TAS1R1/TAS1R3 and all the taste signalling pathway machinery in glioblastoma. Our findings demonstrate that TAS1R2/TAS1R3, TAS1R1/TAS1R3, and 20 out of the 26 human TAS2Rs are present and active in glioblastoma cells, with expression differences in glioblastoma cells and human tumours. The expression of such a large number of members of this family of receptors, highlight the significance of the taste transduction pathway in this form of brain cancer, where these receptors might be essential for the crosstalk between glioblastoma and its microenvironment.

cancer biology↗

bioRxiv2025

The Insertion of an ATTTC Repeat in an Alu Element Hyperactivates a Primate-Specific Neurodevelopmental Enhancer in Spinocerebellar Ataxia Type 37

Alu are evolutionarily very old primate-specific interspersed repeat elements that constitute [~]11% of the human genome. They are a source of short tandem repeats (STRs), which often expand in size and originate inherited neuromuscular and neurodegenerative disorders. How expanded STR insertion mutations within Alu STRs culminate in disease remains unknown. Here we report an Alu STR located in an intron of DAB1 that functions as a neurodevelopmental enhancer. We demonstrated that an ATTTC repeat insertion in this DAB1 Alu STR, known to cause spinocerebellar ataxia type 37 (SCA37), hyperactivates a neurodevelopmental DAB1 enhancer. Importantly, we showed that neurons derived from SCA37 subjects have higher levels of DAB1 expression and DAB1 overexpression causes abnormal axonal pathfinding in vivo. Overall, these results establish that neuronal dysregulation of a developmental DAB1 Alu STR enhancer contributes to SCA37 pathogenesis, an unexplored mechanism likely acting in many Alu STR diseases, potentially reshaping the therapeutic landscape.

genetics↗