Sympathetic Neurons Promote Small Cell Lung Cancer through the β2-Adrenergic Receptor

Menée à l'aide d'organoïdes et de xénogreffes de cancer du poumon à petites cellules sur des modèles murins, cette étude met en évidence un mécanisme par lequel les neurones du système nerveux sympathique favorisent le développement de la maladie par l'intermédiaire du récepteur bêta

Résumé en anglais

The vagal nerve is linked to tumorigenesis in multiple tissues, including small cell lung cancer (SCLC). However, the role of sympathetic neurons in SCLC development remains unknown. In this study, we observed a significant reduction in tumor growth following chemical denervation of local sympathetic nerves in a mouse model of SCLC. Further study identified that β2-adrenergic receptor (ADRB2) expression on cancer cells mediated the cross-talk with nerve fibers. Genetic deletion or pharmacological inhibition of ADRB2 led to reduced tumor growth and improved survival. Moreover, blocking ADRB2 also reduced the growth of human SCLC organoids and xenografts. Further studies revealed that ADRB2 promoted cancer cell expansion through activating protein kinase A (PKA) signaling. Consistently, inhibition of PKA also reduced the growth of SCLC cells. These findings offer the initial insight into the role played by sympathetic neurons in the development of SCLC and may open a new therapeutic avenue to treat this deadly malignancy.SCLC is highly aggressive, with limited effective treatment options. We show that ablating sympathetic nerves or inhibiting the ADRB2 receptor slows SCLC progression and prolongs survival in mice. Additionally, ADRB2 inhibition reduces the growth of human SCLC organoids and xenografts by disrupting PKA signaling, identifying a new therapeutic target.