Inhibition of Cyclin-dependent Kinase Counteracts Neuron-promoted Bladder and Endometrial Tumorigenesis: A Systematic...

The tumor microenvironment is an indispensable component of tumor development. Although fibroblasts and immune cells have been widely studied in tumorigenesis, the role of neurons in cancer has received limited investigation. This study aimed to evaluate the impact of neural signaling on tumorigenesis across cancer types and identify potential therapeutics for neuron-associated tumor development.

A systematic analysis was performed using the Neuro_Cancer database (https://bio-bigdata.hrbmu.edu.cn/Neuro_Cancer/) and its integrated tools, including neural signal activity, clinical survival, neuro-immune interaction, drug association, and spatial transcriptomic pattern analyses. These analyses were applied across cancer types to identify those strongly influenced by neural activity. Experimental validation was conducted using human bladder and endometrial cancer cell lines co-cultured with neurons, followed by treatment with the cyclin-dependent kinase inhibitor RO-3306.

Prognostic analysis identified bladder, thyroid, and endometrial cancers as tumor types strongly influenced by neural activity. Heatmap analysis of neural activity demonstrated obvious differences in neural intensity, classified as high, moderate, or low, among these cancer types. Neuro-immune interaction analysis showed that lymphocytes and granulocytes were involved in tumorigenesis associated with high neural activity. Drug association analysis identified RO-3306 as a potential therapeutic candidate for counteracting neuron-supported tumor development. Experimental validation showed that co-culture with neurons increased the proliferation of bladder and endometrial cancer cells, whereas RO-3306 treatment abolished this effect. Spatial transcriptomic analysis revealed that neural activity was highest in the core of bladder and endometrial tumors, followed by the tumor boundary, tumor budding area, and normal tissue.

These bioinformatic and experimental results highlight the importance of neural signaling in the tumorigenesis of bladder, thyroid, and endometrial cancer and indicate that cyclin-dependent kinase inhibitors may counteract neuron-supported tumor development.