Abstract
Advillin (AVIL) is an actin-binding protein expressed in peripheral sensory neurons and Merkel cells, but aberrantly upregulated in several malignancies, including low-grade glioma, glioblastoma, and rhabdomyosarcoma. AVIL’s oncogenic activity and restricted adult tissue expression make it an attractive therapeutic target; however, its physiological function and the safety of AVIL inhibition remain incompletely understood. We evaluated genetic and pharmacologic targeting of Avil using neurobehavioral and somatosensory assays in vivo. Constitutive and conditional Avil knockout mice, generated by exons 7 and 8 deletion, underwent behavioral testing assessing anxiety-related and exploratory behaviors, motor coordination, affective responses, and learning and memory. Nociceptive and tactile sensory function were evaluated alongside histologic analysis of peripheral mechanosensory architecture. In parallel, a first-in-class AVIL inhibitor was assessed in vivo. Avil-deficient mice exhibited normal exploratory and anxiety-related behavior, intact motor coordination, preserved affective responses, and unaltered learning and memory. Loss or pharmacologic inhibition of advillin did not impair nociceptive processing, tactile sensitivity, or peripheral mechanosensory architecture, and histologic abnormalities were not detected. Together, these findings show preserved baseline behavioral and sensory outcomes following lifelong Avil loss, with complementary evidence of tolerability following pharmacologic inhibition under the conditions tested, supporting AVIL as a potentially well-tolerated therapeutic target in cancer.
Authors
Sarah A. Lynch, Martyna Glowczyk-Gluc, Yiwei Wang, Summer Johnson, Xinrui Shi, Abdul-Salam Gidado, Alexis Johnson, Christopher Deppmann, John Lukens, Hui Li
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