Chemotherapy induces epitranscriptomic changes in the choroid plexus
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| Year of publication | 2025 |
| Type | Conference abstract |
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| Description | More than half of chemotherapy patients develop neuropathic pain, an irreversible and debilitating medical condition that significantly impacts patient well-being and survival chances. Our recent study demonstrated that paclitaxel, a widely used and effective chemotherapy drug for solid tumors, directly modifies the inflammatory profile of the choroid plexus. This finding challenges the conventional view of the choroid plexus as a passive barrier and instead suggests it is an active contributor to neuroinflammatory responses during chemotherapy. We view a comprehensive characterization of the choroid plexus in response to chemotherapy as a unique opportunity to shed light on long-standing unresolved mechanisms behind the central side effects of chemotherapeutic agents. To investigate the effects of paclitaxel on the choroid plexus, we performed next-generation sequencing (RNA-seq) on the choroid plexus tissue of an in vivo chemo-pain rat model (male and female) to profile molecular changes at 1 day, 7 days, and 21 days post-treatment. Our initial analysis focused on differential gene expression (DEG) and alternative splicing. From DEG analysis, we observed limited transcriptional changes. Recognizing the unexpected limited transcriptional changes, we turned our attention to alternative splicing, hypothesizing that the paclitaxel might exert its effects through post-transcriptional regulation. We identified significant local splice variants (LSVs) in the choroid plexus at 1- and 21-day post-treatment. Additionally, we identified regulators of alternative splicing, including RNA-binding proteins (RBPs), that were significantly enriched downstream of the target exon in choroid plexus mRNAs exhibiting increased exon skipping. These changes may impact choroid plexus functions such as neuroinflammation, with broader implications for chemotherapy-induced toxicity. Our findings could accelerate the development of more effective therapies targeting both acute and long-term effects of chemotherapy on the brain. |
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