A STAT3-STING-IFN axis controls the metastatic spread of small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by a high metastatic potential with an overall survival rate of ~5%. The transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed by >50% of tumors, including SCLC, but its role in SCLC development and metastasis is unclear. Here, we show that, while STAT3 deletion restricts primary tumor growth, it paradoxically enhances metastatic spread by promoting immune evasion.

Mapping the IMiD-dependent cereblon interactome using BioID-proximity labelling.

Immunomodulatory imide drugs (IMiDs) are central components of therapy for multiple myeloma (MM). IMiDs bind cereblon (CRBN), an adaptor for the CUL4-DDB1-RBX1 E3 ligase to change its substrate specificity and induce degradation of 'neosubstrate' transcription factors that are essential to MM cells. Mechanistic studies to date have largely focussed on mediators of therapeutic activity and insight into clinical IMiD toxicities is less developed.

Ligand-dependent hedgehog signaling maintains an undifferentiated, malignant osteosarcoma phenotype.

TP53 and RB1 loss-of-function mutations are common in osteosarcoma. During development, combined loss of TP53 and RB1 function leads to downregulation of autophagy and the aberrant formation of primary cilia, cellular organelles essential for the transmission of canonical Hedgehog (Hh) signaling. Excess cilia formation then leads to hypersensitivity to Hedgehog (Hh) ligand signaling.

A STAT3 protein complex required for mitochondrial mRNA stability and cancer.

Signal transducer and activator of transcription 3 (STAT3) is a potent transcription factor necessary for life whose activity is corrupted in diverse diseases, including cancer. STAT3 biology was presumed to be entirely dependent on its activity as a transcription factor until the discovery of a mitochondrial pool of STAT3, which is necessary for normal tissue function and tumorigenesis. However, the mechanism of this mitochondrial activity remained elusive.

Potential Avenues for Exosomal Isolation and Detection Methods to Enhance Small-Cell Lung Cancer Analysis.

Around the world, lung cancer has long been the main factor in cancer-related deaths, with small-cell lung cancer (SCLC) being the deadliest form of lung cancer. Cancer cell-derived exosomes and exosomal miRNAs are considered promising biomarkers for diagnosing and prognosis of various diseases, including SCLC. Due to the rapidity of SCLC metastasis, early detection and diagnosis can offer better diagnosis and prognosis and therefore increase the patient's chances of survival.

Circulating Tumour DNA (ctDNA) as a Predictor of Clinical Outcome in Non-Small Cell Lung Cancer Undergoing Targeted Therapies: A Systematic Review and Meta-Analysis.

Background: Liquid biopsy (LB) analysis using (ctDNA)/cell-free DNA (cfDNA) is an emerging alternative to tissue profiling in (NSCLC). LB is used to guide treatment decisions, detect resistance mechanisms, and predicts responses, and, therefore, outcomes. This systematic review and meta-analysis evaluated the impact of LB quantification on clinical outcomes in molecularly altered advanced NSCLC undergoing targeted therapies.

MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat.

Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with an appalling overall survival of less than 5% (Zimmerman et al. J Thor Oncol 14:768-83, 2019). Patients typically respond to front line platinum-based doublet chemotherapy, but almost universally relapse with drug resistant disease.

Generation and multi-dimensional profiling of a childhood cancer cell line atlas defines new therapeutic opportunities.

Pediatric solid and central nervous system tumors are the leading cause of cancer-related death among children. Identifying new targeted therapies necessitates the use of pediatric cancer models that faithfully recapitulate the patient's disease. However, the generation and characterization of pediatric cancer models has significantly lagged behind adult cancers, underscoring the urgent need to develop pediatric-focused cell line resources.

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes.

Precise control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development and frequently corrupted in cancer. By coupling a cell surface readout of bivalent MHC class I gene expression with whole-genome CRISPR-Cas9 screens, we identify specific roles for MTF2-PRC2.1, PCGF1-PRC1.

Lineage-restricted neoplasia driven by Myc defaults to small cell lung cancer when combined with loss of p53 and Rb in the airway epithelium.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by loss of function TP53 and RB1 mutations in addition to mutations in other oncogenes including MYC. Overexpression of MYC together with Trp53 and Rb1 loss in pulmonary neuroendocrine cells of the mouse lung drives an aggressive neuroendocrine low variant subtype of SCLC. However, the transforming potential of MYC amplification alone on airway epithelium is unclear.

STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and Its Deficiency Induces Glucose Intolerance in Obesity.

Most obese and insulin-resistant individuals do not develop diabetes. This is the result of the capacity of β-cells to adapt and produce enough insulin to cover the needs of the organism. The underlying mechanism of β-cell adaptation in obesity, however, remains unclear.

Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages.

Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation.

STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression.

Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) on macrophages induces a robust pro-inflammatory response that is dependent on metabolic reprogramming. These innate metabolic changes have been compared to aerobic glycolysis in tumour cells. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming are unknown.

Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling.

Ligand-dependent activation of Hedgehog (Hh) signaling in cancer occurs without mutations in canonical pathway genes. Consequently, the genetic basis of Hh pathway activation in adult solid tumors, such as small-cell lung cancer (SCLC), is unknown. Here we show that combined inactivation of Trp53 and Rb1, a defining genetic feature of SCLC, leads to hypersensitivity to Hh ligand in vitro, and during neural tube development in vivo.

Constitutive STAT3 Serine Phosphorylation Promotes Helicobacter-Mediated Gastric Disease.

Gastric cancer is associated with chronic inflammation (gastritis) triggered by persistent Helicobacter pylori (H. pylori) infection. Elevated tyrosine phosphorylation of the latent transcription factor STAT3 is a feature of gastric cancer, including H.

STAT3-driven hematopoiesis and lymphopoiesis abnormalities are dependent on serine phosphorylation.

Deregulated activation of the latent transcription factor STAT3 has been implicated in the pathogenesis of myeloproliferative and lymphoproliferative hematologic disorders. The uncontrolled activation of STAT3 has traditionally been assigned to its elevated phosphorylation at tyrosine 705 (pY) and associated nuclear transcriptional activity. By contrast, a transcriptional role for serine 727 phosphorylation (pS) of STAT3 has recently emerged, suggesting that pS may account for the pathological activity of STAT3 in certain disease settings.

A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma.

Medulloblastoma is the most common malignant brain tumor in children and represents 20% of all pediatric central nervous system neoplasms. While advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represent a major health care burden and have led to ongoing efforts to find effective targeted treatments. There is a well-recognized male bias in medulloblastoma diagnosis, although the mechanism remains unknown.

Serine-Phosphorylated STAT3 Promotes Tumorigenesis via Modulation of RNA Polymerase Transcriptional Activity.

Deregulated activation of the latent oncogenic transcription factor STAT3 in many human epithelial malignancies, including gastric cancer, has invariably been associated with its canonical tyrosine phosphorylation and enhanced transcriptional activity. By contrast, serine phosphorylation (pS) of STAT3 can augment its nuclear transcriptional activity and promote essential mitochondrial functions, yet the role of pS-STAT3 among epithelial cancers is ill-defined. Here, we reveal that genetic ablation of pS-STAT3 in the spontaneous gastric cancer mouse model and human gastric cancer cell line xenografts abrogated tumor growth that coincided with reduced proliferative potential of the tumor epithelium.

Therapeutically exploiting STAT3 activity in cancer - using tissue repair as a road map.

The tightly orchestrated temporal and spatial control of signal transducer and activator of transcription 3 (STAT3) activity in epithelial, immune and stromal cells is critical for wound healing and tissue repair. Excessive STAT3 activation within cancer cells and cells of the tumour microenvironment can be viewed as a neoplastic mimic of an inflammation-driven repair response that collectively promotes tumour progression. In addition to the canonical transcriptional pathways by which STAT3 promotes stem cell-like characteristics, survival, proliferation, metastatic potential and immune evasion, cytoplasmic STAT3 activity fuels tumour growth by metabolic and other non-transcriptional mechanisms.

Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2.

Toll-like receptors (TLRs) play critical roles in host defense after recognition of conserved microbial- and host-derived components, and their dysregulation is a common feature of various inflammation-associated cancers, including gastric cancer (GC). Despite the recent recognition that metabolic reprogramming is a hallmark of cancer, the molecular effectors of altered metabolism during tumorigenesis remain unclear. Here, using bioenergetics function assays on human GC cells, we reveal that ligand-induced activation of TLR2, predominantly through TLR1/2 heterodimer, augments both oxidative phosphorylation (OXPHOS) and glycolysis, with a bias toward glycolytic activity.

Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer.

Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain.

STAT3: a multifaceted oncoprotein.

Signal transducer and activator of transcription (STAT) 3 is a key signalling protein engaged by a multitude of growth factors and cytokines to elicit diverse biological outcomes including cellular growth, differentiation, and survival. The complete loss of STAT3 is not compatible with life and even partial loss of function mutations lead to debilitating pathologies like hyper IgE syndrome. Conversely, augmented STAT3 activity has been reported in as many as 50% of all human tumours.

Discovery and Validation of Novel Protein Biomarkers in Ovarian Cancer Patient Urine.

Purpose: For the vast majority of ovarian cancer patients, optimal surgical debulking remains a key prognostic factor associated with improved survival. A standardized, biomarker-based test, to preoperatively discriminate benign from malignant disease and inform appropriate patient triage, is highly desirable. However, no fit-for-purpose biomarkers have yet been identified.