The Role of Inflammasome-Associated Innate Immune Receptors in Cancer.

Dysregulated activation of the innate immune system is a critical driver of chronic inflammation that is associated with at least 30% of all cancers. Innate immunity can also exert tumour-promoting effects (e.g.

Evaluation of Needles in Endoscopic Ultrasound-Guided Tissue Acquisition of Pancreatic Cancer for Genetic Yield and Quality.

Background: Endoscopic ultrasound-guided fine needle biopsy (FNB) is the gold standard in tissue acquisition of pancreatic ductal adenocarcinoma (PDAC). There is a paucity of evidence of the impact of needle type or size on the genetic yield and quality.

Methods: Patients 18 years and older with PDAC who underwent FNB were retrospectively identified from a single database from 2016 to 2021.

Patient-Derived Xenografts: A Valuable Preclinical Model for Drug Development and Biomarker Discovery.

Patient-derived xenografts (PDXs), established by implanting patient tumor cells into immunodeficient mice, offer a platform for faithfully replicating human tumors. They closely mimic the histopathology, genomics, and drug sensitivity of patient tumors. This chapter highlights the versatile applications of PDXs, including studying tumor biology, metastasis, and chemoresistance, as well as their use in biomarker identification, drug screening, and personalized medicine.

Cytosolic DNA sensor AIM2 promotes KRAS-driven lung cancer independent of inflammasomes.

Constitutively active KRAS mutations are among the major drivers of lung cancer, yet the identity of molecular co-operators of oncogenic KRAS in the lung remains ill-defined. The innate immune cytosolic DNA sensor and pattern recognition receptor (PRR) Absent-in-melanoma 2 (AIM2) is best known for its assembly of multiprotein inflammasome complexes and promoting an inflammatory response. Here, we define a role for AIM2, independent of inflammasomes, in KRAS-addicted lung adenocarcinoma (LAC).

Circulating Tumor DNA Is an Accurate Diagnostic Tool and Strong Prognostic Marker in Pancreatic Cancer.

Objective: The objectives of the study are to investigate the sensitivity and specificity of circulating tumor DNA (ctDNA) for the diagnosis of pancreatic cancer and to assess the utility of ctDNA as a prognostic marker in this disease.

Methods: Cell-free DNA was extracted from plasma of patients who underwent endoscopic ultrasound fine-needle aspiration or surgical resections for pancreatic cancer. The cell-free DNA was then analyzed using droplet digital polymerase chain reaction for KRAS G12/13 mutations.

The protease ADAM17 at the crossroads of disease: revisiting its significance in inflammation, cancer, and beyond.

The protease A Disintegrin And Metalloproteinase 17 (ADAM17) plays a central role in the pathophysiology of several diseases. ADAM17 is involved in the cleavage and shedding of at least 80 known membrane-tethered proteins, which subsequently modulate several intracellular signaling pathways, and therefore alter cell behavior. Dysregulated expression and/or activation of ADAM17 has been linked to a wide range of autoimmune and inflammatory diseases, cancer, and cardiovascular disease.

An In Vitro Model for Assessing Acute Lung Injury During Pancreatitis Development Using Primary Mouse Cell Co-cultures.

Acute pancreatitis is a serious inflammatory disease of the pancreas that can lead to lung injury. Despite extensive research, the mechanisms underlying this complication are ill-defined. In recent years, in vitro co-culture systems have emerged as powerful tools for studying complex interactions between different cell types in disease.

Th1 Cells Alter the Inflammatory Signature of IL-6 by Channeling STAT Transcription Factors to Alu-like Retroelements.

Cytokines that signal via STAT1 and STAT3 transcription factors instruct decisions affecting tissue homeostasis, antimicrobial host defense, and inflammation-induced tissue injury. To understand the coordination of these activities, we applied RNA sequencing, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing to identify the transcriptional output of STAT1 and STAT3 in peritoneal tissues from mice during acute resolving inflammation and inflammation primed to drive fibrosis. Bioinformatics focused on the transcriptional signature of the immunomodulatory cytokine IL-6 in both settings and examined how profibrotic IFN-γ-secreting CD4+ T cells altered the interpretation of STAT1 and STAT3 cytokine cues.

Targeting IL-6 trans-signalling: past, present and future prospects.

Interleukin-6 (IL-6) is a key immunomodulatory cytokine that affects the pathogenesis of diverse diseases, including autoimmune diseases, chronic inflammatory conditions and cancer. Classical IL-6 signalling involves the binding of IL-6 to the membrane-bound IL-6 receptor α-subunit (hereafter termed 'mIL-6R') and glycoprotein 130 (gp130) signal-transducing subunit. By contrast, in IL-6 trans-signalling, complexes of IL-6 and the soluble form of IL-6 receptor (sIL-6R) signal via membrane-bound gp130.

The cytosolic DNA sensor AIM2 promotes Helicobacter-induced gastric pathology via the inflammasome.

Helicobacter pylori (H. pylori) infection can trigger chronic gastric inflammation perpetuated by overactivation of the innate immune system, leading to a cascade of precancerous lesions culminating in gastric cancer. However, key regulators of innate immunity that promote H.

G12D Mutation Subtype in Pancreatic Ductal Adenocarcinoma: Does It Influence Prognosis or Stage of Disease at Presentation?

: G12D mutation subtype is present in over 40% of pancreatic ductal adenocarcinoma (PDAC), one of the leading global causes of cancer death. This retrospective cohort study aims to investigate whether detection of the G12D mutation subtype in PDAC patients is a determinant of prognosis across all stages of disease. : We reviewed the medical records of 231 patients presenting with PDAC at a large tertiary hospital, and compared survival using the Kaplan Meier, log-rank test and Cox proportional hazards regression model.

Blockade of the protease ADAM17 ameliorates experimental pancreatitis.

Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalization. Despite the global health burden of pancreatitis, currently, there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinase 17 (ADAM17) mediates inflammatory responses through shedding of bioactive inflammatory cytokines and mediators, including tumor necrosis factor α (TNFα) and the soluble interleukin (IL)-6 receptor (sIL-6R), the latter of which drives proinflammatory IL-6 trans-signaling.

Cross-talk between IL-6 trans-signaling and AIM2 inflammasome/IL-1β axes bridge innate immunity and epithelial apoptosis to promote emphysema.

Pulmonary emphysema is associated with dysregulated innate immune responses that promote chronic pulmonary inflammation and alveolar apoptosis, culminating in lung destruction. However, the molecular regulators of innate immunity that promote emphysema are ill-defined. Here, we investigated whether innate immune inflammasome complexes, comprising the adaptor ASC, Caspase-1 and specific pattern recognition receptors (PRRs), promote the pathogenesis of emphysema.

Toll-like Receptor 9 Promotes Initiation of Gastric Tumorigenesis by Augmenting Inflammation and Cellular Proliferation.

Background & Aims: Gastric cancer (GC) is strongly linked with chronic gastritis after Helicobacter pylori infection. Toll-like receptors (TLRs) are key innate immune pathogenic sensors that mediate chronic inflammatory and oncogenic responses. Here, we investigated the role of TLR9 in the pathogenesis of GC, including Helicobacter infection.

Context-dependent functions of pattern recognition receptors in cancer.

The immune system plays a critical role in shaping all facets of cancer, from the early initiation stage through to metastatic disease and resistance to therapy. Our understanding of the importance of the adaptive arm of the immune system in antitumour immunity has led to the implementation of immunotherapy with immune checkpoint inhibitors in numerous cancers, albeit with differing efficacy. By contrast, the clinical utility of innate immunity in cancer has not been exploited, despite dysregulated innate immunity being a feature of at least one-third of all cancers associated with tumour-promoting chronic inflammation.

Inflammasome-Associated Gastric Tumorigenesis Is Independent of the NLRP3 Pattern Recognition Receptor.

Inflammasomes are important multiprotein regulatory complexes of innate immunity and have recently emerged as playing divergent roles in numerous inflammation-associated cancers. Among these include gastric cancer (GC), the third leading cause of cancer-associated death worldwide, and we have previously discovered a pro-tumorigenic role for the key inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) in the spontaneous genetic mouse model for GC. However, the identity of the specific pattern recognition receptors (PRRs) that activate tumor-promoting inflammasomes during GC is unknown.

EUS-FNA Biopsies to Guide Precision Medicine in Pancreatic Cancer: Results of a Pilot Study to Identify Wild-Type Tumours for Targeted Therapy.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death and lacks effective treatment options. Diagnostic endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsies represent an appealing source of material for molecular analysis to inform targeted therapy, as they are often the only available tissue for patients presenting with PDAC irrespective of disease stage. However, EUS-FNA biopsies are typically not used to screen for precision medicine studies due to concerns about low tissue yield and quality.

Oncogenic dependency on STAT3 serine phosphorylation in KRAS mutant lung cancer.

The oncogenic potential of the latent transcription factor signal transducer and activator of transcription (STAT)3 in many human cancers, including lung cancer, has been largely attributed to its nuclear activity as a tyrosine-phosphorylated (pY site) transcription factor. By contrast, an alternate mitochondrial pool of serine phosphorylated (pS site) STAT3 has been shown to promote tumourigenesis by regulating metabolic processes, although this has been reported in only a restricted number of mutant RAS-addicted neoplasms. Therefore, the involvement of STAT3 serine phosphorylation in the pathogenesis of most cancer types, including mutant KRAS lung adenocarcinoma (LAC), is unknown.

Complete loss of miR-200 family induces EMT associated cellular senescence in gastric cancer.

The EMT (epithelial-to-mesenchymal-transition) subtype of gastric cancer (GC) is associated with poor treatment responses and unfavorable clinical outcomes. Despite the broad physiological roles of the micro-RNA (miR)-200 family, they largely serve to maintain the overall epithelial phenotype. However, during late-stage gastric tumorigenesis, members of the miR-200 family are markedly suppressed, resulting in the transition to the mesenchymal state and the acquisition of invasive properties.

The EUS molecular evaluation of pancreatic cancer: A prospective multicenter cohort trial.

Background And Objectives: Patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (A-PDAC) are not candidates for surgical resection and are often offered palliative chemotherapy. The ready availability of a safe and effective tumor sampling technique to provide material for both diagnosis and comprehensive genetic profiling is critical for informing precision medicine in A-PDAC, thus potentially increasing survival. The aim of this study is to examine the feasibility and benefits of routine comprehensive genomic profiling (CGP) of A-PDAC using EUS-FNA material.

STAT3-mediated upregulation of the AIM2 DNA sensor links innate immunity with cell migration to promote epithelial tumourigenesis.

Objective: The absent in melanoma 2 (AIM2) cytosolic pattern recognition receptor and DNA sensor promotes the pathogenesis of autoimmune and chronic inflammatory diseases via caspase-1-containing inflammasome complexes. However, the role of AIM2 in cancer is ill-defined.

Design: The expression of AIM2 and its clinical significance was assessed in human gastric cancer (GC) patient cohorts.