Hilton, M. | Search bioRxiv

bioRxiv2021

STING suppresses cancer pain via immune and neuronal modulation

Agonists of the innate immune regulator stimulator of interferon genes (STING) have shown great efficacy in promoting antitumor immunity in preclinical models, leading to their exploration in cancer immunotherapy trials. Patients with advanced stage cancers frequently suffer from severe pain as a result of bone metastasis and bone destruction, for which there is no efficacious treatment. Here, using multiple mouse models of metastatic bone cancer, we report that STING agonists confer remarkable protection against cancer pain, bone destruction, and local tumor burden. Repeated systemic administration of STING agonists robustly attenuated bone cancer-induced pain symptoms and improved locomotor function. Interestingly, STING agonists provided acute pain relief through direct neuronal modulation, as ex vivo incubation of STING agonists reduced excitability of pain-sensing nociceptive neurons from tumor-bearing mice. In addition, STING agonists protected local bone destruction and reduced local tumor burden through modulation of osteoclast and immune cell function in the tumor microenvironment, providing long-term cancer pain relief. Finally, these in vivo effects were dependent on host-intrinsic STING and Ifnar1. Overall, STING activation provides unique advantages in controlling metastatic bone cancer pain through distinct and synergistic actions on nociceptors, immune cells, and osteoclasts.

cancer biology↗

bioRxiv2019

Homeostasis of the intervertebral disc requires regulation of STAT3 signaling by the adhesion G-protein coupled receptor ADGRG6

Degenerative changes of the intervertebral disc (IVD) are a leading cause of disability affecting humans worldwide. While this is primarily attributed to trauma and aging, genetic variation is associated with disc degeneration in humans. However, the precise mechanisms driving the initiation and progression of disease remain elusive due to a paucity of genetic animal models. Here, we discuss a novel genetic mouse model of endplate-oriented disc degeneration. We show that the adhesion G-protein coupled receptor G6 (ADGRG6) mediates several anabolic and catabolic factors, fibrotic collagen genes, pro-inflammatory pathways, and mechanical properties of the IVD, prior to the onset of overt histopathology of these tissues. Furthermore, we found increased IL-6/STAT3 activation in the IVD and demonstrate that treatment with a chemical inhibitor of STAT3 activation ameliorates disc degeneration in these mutant mice. These findings establish ADGRG6 as a critical regulator of homeostasis of adult disc homeostasis and implicate ADGRG6 and STAT3 as promising therapeutic targets for degenerative joint diseases.\n\nAuthor summaryDegenerative changes of the intervertebral disc (IVD) are a leading cause of disability affecting humans worldwide. While this is primarily attributed to trauma and aging, genetic variation is associated with disc degeneration in humans. However, the precise mechanisms driving the initiation and progression of disease remain elusive due to a paucity of genetic animal models. Here, we discuss a novel genetic mouse model of endplate-oriented disc degeneration. We show that the adhesion G-protein coupled receptor G6 (ADGRG6) mediates fibrotic collagen expression, causing increased mechanical stiffness of the IVD prior to the onset of histopathology in adult mice. Furthermore, we found increased IL-6/STAT3 activation in the IVD and demonstrate that treatment with a chemical inhibitor of STAT3 activation ameliorates disc degeneration in these mutant mice. Our results demonstrate that ADGRG6 regulation of STAT3 signaling is important for IVD homeostasis, indicating potential therapeutic targets for degenerative joint disorders.

developmental biology↗