RESUMO
Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV- HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo. A number of druggable pathways, including PPAR and Wnt, were modulated in response to HPVE6E7 loss. Fenofibrate showed significant anti-proliferative effects in a panel of HPV+ cancer cell lines. Additionally, fenofibrate impaired tumor growth as monotherapy and potentiated the activity of cisplatin in a pre-clinical HPV+ animal model. Systemic fenofibrate treatment induced p53 protein accumulation, and surprisingly, re-programmed the tumor-immune microenvironment to drive immune cell infiltration. Since fenofibrate is FDA-approved with a favorable long-term safety record, repositioning of this drug, as a single agent or in combination with cisplatin or checkpoint blockade, for the HPV+ HNSCC setting should be prioritized.
RESUMO
Neural circuits underlying brain functions are vulnerable to damage, including ischemic injury, leading to neuronal loss and gliosis. Recent technology of direct conversion of endogenous astrocytes into neurons in situ can simultaneously replenish the neuronal population and reverse the glial scar. However, whether these newly reprogrammed neurons undergo normal development, integrate into the existing neuronal circuit, and acquire functional properties specific for this circuit is not known. We investigated the effect of NeuroD1-mediated in vivo direct reprogramming on visual cortical circuit integration and functional recovery in a mouse model of ischemic injury. After performing electrophysiological extracellular recordings and two-photon calcium imaging of reprogrammed cells in vivo and mapping the synaptic connections formed onto these cells ex vivo, we discovered that NeuroD1 reprogrammed neurons were integrated into the cortical microcircuit and acquired direct visual responses. Furthermore, following visual experience, the reprogrammed neurons demonstrated maturation of orientation selectivity and functional connectivity. Our results show that NeuroD1-reprogrammed neurons can successfully develop and integrate into the visual cortical circuit leading to vision recovery after ischemic injury.
RESUMO
Visual systems have evolved to recognize and extract features from complex scenes using limited sensory information. Contour perception is essential to this process and can occur despite breaks in the continuity of neighboring features. Such robustness of the animal visual system to degraded or occluded shapes may also give rise to an interesting phenomenon of optical illusions. These illusions provide a great opportunity to decipher neural computations underlying contour integration and object detection. Kanizsa illusory contours have been shown to evoke responses in the early visual cortex despite the lack of direct receptive field activation. Recurrent processing between visual areas has been proposed to be involved in this process. However, it is unclear whether higher visual areas directly contribute to the generation of illusory responses in the early visual cortex. Using behavior, in vivo electrophysiology, and optogenetics, we first show that the primary visual cortex (V1) of male mice responds to Kanizsa illusory contours. Responses to Kanizsa illusions emerge later than the responses to the contrast-defined real contours in V1. Second, we demonstrate that illusory responses are orientation-selective. Finally, we show that top-down feedback controls the neural correlates of illusory contour perception in V1. Our results suggest that higher-order visual areas may fill in the missing information in the early visual cortex necessary for illusory contour perception.SIGNIFICANCE STATEMENT Perception of the Kanizsa illusory contours is impaired in neurodevelopmental disorders such as schizophrenia, autism, and Williams syndrome. However, the mechanism of the illusory contour perception is poorly understood. Here we describe the behavioral and neural correlates of Kanizsa illusory contours perception in mice, a genetically tractable model system. We show that top-down feedback controls the neural responses to Kanizsa illusion in V1. To our knowledge, this is the first description of the neural correlates of the Kanizsa illusion in mice and the first causal demonstration of their regulation by top-down feedback.
