Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer.

Metastasis occurs frequently after resection of pancreatic cancer (PaC). In this study, we hypothesized that multi-parametric analysis of pre-metastatic liver biopsies would classify patients according to their metastatic risk, timing and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PaC and 19 control patients with non-cancerous pancreatic lesions were analyzed, combining metabolomic, tissue and single-cell transcriptomics and multiplex imaging approaches. Patients were followed prospectively (median 3 years) and classified into four recurrence groups; early (<6 months after resection) or late (>6 months after resection) liver metastasis (LiM); extrahepatic metastasis (EHM); and disease-free survivors (no evidence of disease (NED)). Overall, PaC livers exhibited signs of augmented inflammation compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LiM were characterized by scant T cell lobular infiltration, less steatosis and higher levels of citrullinated H3 compared to patients who developed EHM, who had overexpression of interferon target genes (MX1 and NR1D1) and an increase of CD11B+ natural killer (NK) cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B+ NK cells, differentiated patients with early-onset LiM from those with late-onset LiM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine-learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multi-parametric profiling of liver biopsies at the time of PaC diagnosis may determine metastatic risk and organotropism and guide clinical stratification for optimal treatment selection.

Society of General Physiologists Symposium on "Ion Channels and Transporters in Immunity, Inflammation and Antitumor Immunity" (held online on September 11, 2020).

Ion channels and ionic transporters are expressed in every cell in the body, including the cells of the immune system. This international meeting was dedicated to some of the latest advances in the field and covered a range of topics in seven presentations. Zinc transport by the ZIP7 transporter expressed in the endoplasmic reticulum, transporting Zn2+ into the cytoplasm, was shown to be essential for B-cell development and functioning. Consequently, complete loss of ZIP7 was likely to be fatal (Sophie Hambleton). The protein kinase domain of TRPM7 cation channel was involved in proinflammatory T-cell differentiation (Susanna Zierler). A particularly novel development focused on 'optogenetic immunotherapy' involving photo-switchable Ca2+ (STIM1/ORAI) signaling in T-cells enabling spatially and temporally distinct immune signaling including transcriptional reprogramming (Yubin Zhou). Starting with genetic screening and functional genomics, T-cells were shown to express a volume-regulated anion (Cl-) channel (with LRRC8C and LRRC8A as essential components). The channel's activity controlled production of inflammatory cytokines and autoimmunity in the murine spinal cord (Axel Concepcion). Ca2+ signaling induced by CRAC/ORAI in TH17 lymphocytes in neuroinflammatory spinal cord was studied further by confocal imaging. Treg cells were found to inhibit TH17 functioning, in part, by suppressing Ca2+ signaling. This approach could open up a novel immunotherapy method (Michael Cahalan). S1PR (a GPCR that mediates S1P signaling) and SPNS2, a lymphatic S1P transporter, controlling T-cell trafficking in lymph nodes were characterized by Susan Schwab. Finally, pathogenic/damaged cytosolic DNA binding to the cyclic GMP-AMP synthase protein to enable synthesis of the secondary messenger cyclic GMP-AMP, leading to immune response involving production of cytokines and activation of natural killer cells was demonstrated by David Raulet. Thus, the meeting highlighted how studies of cellular ion channels and ionic transporters could elucidate both the understanding of immune cell functioning and, ultimately, improve its clinical management.