Summary Ankylosing spondylitis (AS) is a common immune‐mediated inflammatory arthritis with a strong genetic predisposition. We review recent data from genetic and animal studies highlighting the importance of Type 17 immune responses. Furthermore, the efficacy (or lack thereof) of different anti‐cytokine monoclonal antibodies has highlighted the diversity of Type 17 immune cells and cytokines critical to AS and related spondyloarthritis pathogenesis. Recent studies have strongly implicated the gut microbiome in AS. Finally, we propose that the local metabolic environment of the joint may have a key role in driving AS, and present a novel model of AS pathogenesis.

Melanoma is one of the most aggressive and treatment-resistant human cancers. The two-pore channel 2 (TPC2) is located on late endosomes, lysosomes and melanosomes. Here, we characterized how TPC2 knockout (KO) affected human melanoma cells derived from a metastatic site. TPC2 KO increased these cells’ ability to invade the extracelullar matrix and was associated with the increased expression of mesenchymal markers ZEB-1, Vimentin and N-Cadherin, and the enhanced secretion of MMP9. TPC2 KO also activated genes regulated by YAP/TAZ, which are key regulators of tumourigenesis and metastasis. Expression levels of ORAI1, a component of store-operated Ca2+ entry (SOCE), and PKC-βII, part of the HIPPO pathway that negatively regulates YAP/TAZ activity, were reduced by TPC2 KO and RNA interference knockdown. We propose a cellular mechanism mediated by ORAI1/Ca2+/PKC-βII to explain these findings. Highlighting their potential clinical significance, patients with metastatic tumours showed a reduction in TPC2 expression. Our research indicates a novel role of TPC2 in melanoma. While TPC2 loss may not activate YAP/TAZ target genes in primary melanoma, in metastatic melanoma it could activate such genes and increase cancer aggressiveness. These findings aid the understanding of tumourigenesis mechanisms and could provide new diagnostic and treatment strategies for skin cancer and other metastatic cancers.