Vasoactive intestinal peptide gene polymorphisms, associated with its serum levels, predict treatment requirements in early rheumatoid arthritis

We previously reported that early arthritis (EA) patients with low vasoactive intestinal peptide (VIP) serum levels demonstrate a worse clinical disease course. In this study, we analysed whether variants in the VIP gene correlated with its serum levels and clinical EA parameters. The VIP gene was sequenced in patients with extremely high/low VIP levels, measured by enzyme immunoassay. Sixteen single nucleotide polymorphisms (SNPs) were diferentially distributed between both groups, which were subsequently genotyped in two patients’ sets. We observed that patients with rs688136 CC genotype showed higher VIP levels in both discovery (n=91; p=0.033) and validation populations (n=131; p=0.007). This efect was attenuated by the presence of minor alleles rs35643203 and rs12201140, which showed a clear trend towards low VIP level association (p=0.118 and p=0.049, respectively). Functional studies with miR-205-5p, which has a target site in the 3′ UTR close to rs688136, revealed a miRNA-mediated regulatory mechanism explaining the higher VIP gene expression in homozygous patients. Moreover, patients with an rs688136 CC genotype and no minor alleles of the other polymorphisms required less treatment (p=0.009). We concluded that the identifcation of polymorphisms associated with VIP serum levels would complement the clinical assessment of the disease severity in rheumatoid arthritis patients

A primer on cancer-associated fibroblast mechanics and immunosuppressive ability

Cancer-associated fibroblasts (CAFs) are a major point of interest in modern oncology. Their interest resides in their ability to favor tumor growth without carrying genetic mutations. From a translational standpoint, they are potential therapeutic targets, particularly for hard-to-treat solid cancers. CAFs can be defined as non-tumor cells within the tumor microenvironment that have the morphological traits of fibroblasts, are negative for lineage-specific markers (e.g., leukocyte, endothelium), and enhance tumor progression in a multi-pronged manner. Two often-mentioned aspects of CAF biology are their ability to alter the mechanics and architecture of the tumor microenvironment, and also to drive local immunosuppression. These two aspects are the specific focus of this work, which also contains a brief summary of novel therapeutic interventions under study to normalize or eliminate CAFs from the tumor microenvironment.This work was funded by the Spanish Ministry of Science and Innovation [PID2020-116232RB-I00, ECRIN-M3] from AECC/AIRC/CRUK. Instituto de Biologia Molecular y Celular del Cancer is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Ministry of Education of the Castilla–León Government [CLC–2017–01].

Tyrosine phosphorylation of the myosin regulatory light chain controls non-muscle myosin II assembly and function in migrating cells

Active non-muscle myosin II (NMII) enables migratory cell polarization and controls dynamic cellular processes, such as focal adhesion formation and turnover and cell division. Filament assembly and force generation depend on NMII activation through the phosphorylation of Ser19 of the regulatory light chain (RLC). Here, we identify amino acid Tyr (Y) 155 of the RLC as a novel regulatory site that spatially controls NMII function. We show that Y155 is phosphorylated in vitro by the Tyr kinase domain of epidermal growth factor (EGF) receptor. In cells, phosphorylation of Y155, or its phospho-mimetic mutation (Glu), prevents the interaction of RLC with the myosin heavy chain (MHCII) to form functional NMII units. Conversely, Y155 mutation to a structurally similar but non-phosphorylatable amino acid (Phe) restores the more dynamic cellular functions of NMII, such as myosin filament formation and nascent adhesion assembly, but not those requiring stable actomyosin bundles, e.g., focal adhesion elongation or migratory front-back polarization. In live cells, phospho-Y155 RLC is prominently featured in protrusions, where it prevents NMII assembly. Our data indicate that Y155 phosphorylation constitutes a novel regulatory mechanism that contributes to the compartmentalization of NMII assembly and function in live cells.C.L.-G. is supported by a predoctoral fellowship from the Junta de Castilla y León. M.M.-S. is supported by a predoctoral fellowhip from the AECC. This work was funded by the following grants: Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia (CLC–2017–01) from the Junta de Castilla-León with FEDER funds (Spain); SAF2014-54705-R and SAF2017-87408-R from MINECO (Spain); CIVP16A1831 from the Ramón Areces Foundation (Spain); 14-BBM-340 from the BBVA Foundation (Spain); and IDEAS-VICE18 from the Asociacion Española Contra el Cáncer (AECC, Spain) to M.V.-M.; NIH GM 037537 (D.F.H.); and K22HL131869 (S.M.H.) and the Intramural Research Program (J.R.S.) of the National Heart, Lung, and Blood Institute, NIH.Peer reviewe