RESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies1. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leading to dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC2, but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-1ß (IL-1ß)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E2 (PGE2) and tumour necrosis factor (TNF). Physical proximity with IL-1ß+ TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE2 or IL-1ß activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE2-IL-1ß axis may enable preventive or therapeutic strategies for reprogramming of immune dynamics in pancreatic cancer.
Assuntos
Inflamação , Interleucina-1beta , Neoplasias Pancreáticas , Macrófagos Associados a Tumor , Humanos , Carcinogênese , Carcinoma Ductal Pancreático/complicações , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Dinoprostona/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral , Fatores de Necrose Tumoral/metabolismo , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologiaRESUMO
The Mediterranean Region is one of the world's biodiversity hot-spots, which is also characterized by high level of endemism. Approximately 2100 species of leaf beetle (Coleoptera; Chrysomelidae) are known from this area, a number that increases year after year and represents 5/6% of the known species. These features, associated with the urgent need to develop a DNA-based species identification approach for a broad spectrum of leaf beetle species, prompted us to develop a database of nucleotide sequences, with a solid taxonomic background, for all the Chrysomelidae Latreille, 1802 sensu latu inhabiting the Mediterranean region. The Mediterranean Chrysomelidae Barcoding project, which has started in 2009, involves more than fifty entomologists and molecular biologists from different European countries. Numerous collecting campaigns have been organized during the first seven years of the project, which led to the collection of more than 5000 leaf beetle specimens. In addition, during these collecting campaigns two new allochthonous species for Europe, namely Ophraella communa LeSage, 1986 and Colasposoma dauricum Mannerheim, 1849, were intercepted and some species new to science were discovered (e.g., Pachybrachis sassii Montagna, 2011 and Pachybrachis holerorum Montagna et al., 2013). DNA was extracted from 1006 specimens (~13% of the species inhabiting the Mediterranean region) and a total of 910 cox1 gene sequences were obtained (PCR amplification efficiency of 93.8%). Here we report the list of the barcoded subfamilies, genera and the number of species for which cox1 gene sequences were obtained; the metadata associated with each specimen and a list of problematic species for which marker amplification failed. In addition, the nucleotide divergence within and between species and genera was estimated and values of intraspecific nucleotide divergence greater than the average have been discussed. Cryptocephalus quadripunctatus G. A. Olivier, 1808, Cryptocephalus rugicollis G. A. Olivier, 1791 and Exosoma lusitanicum Linnaeus, 1767) are representatives of these cases.
RESUMO
Colasposoma dauricum Mannerheim, 1849, a species native to the Eastern Asia, is newly found in Piedmont-Italy. This discovery constitutes the first report of the species from Europe, as well as its first report from outside the original area. The general habitus of the species, the distribution in Italy based on the current knowledge, ecological notes and a reference cox1 gene sequences are reported in the present note.