ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors.
Subject(s)
Carcinoma, Pancreatic Ductal/immunology , Macrophages/immunology , Models, Immunological , Neoplasm Proteins/immunology , Pancreatic Neoplasms/immunology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/immunology , T-Lymphocytes/immunology , Adult , Aniline Compounds/pharmacology , Animals , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Female , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Immunity, Cellular/drug effects , Immunity, Cellular/genetics , Macrophages/pathology , Male , Mice , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics , T-Lymphocytes/pathology , Xenograft Model Antitumor AssaysABSTRACT
Cell migration through the brain parenchyma underpins neurogenesis and glioblastoma (GBM) development. Since GBM cells and neuroblasts use the same migratory routes, mechanisms underlying migration during neurogenesis and brain cancer pathogenesis may be similar. Here, we identify a common pathway controlling cell migration in normal and neoplastic cells in the CNS. The nuclear scaffold protein promyelocytic leukemia (PML), a regulator of forebrain development, promotes neural progenitor/stem cell (NPC) and neuroblast migration in the adult mouse brain. The PML pro-migratory role is active also in transformed mouse NPCs and in human primary GBM cells. In both normal and neoplastic settings, PML controls cell migration via Polycomb repressive complex 2 (PRC2)-mediated repression of Slits, key regulators of axon guidance. Finally, a PML/SLIT1 axis regulates sensitivity to the PML-targeting drug arsenic trioxide in primary GBM cells. Taken together, these findings uncover a drug-targetable molecular axis controlling cell migration in both normal and neoplastic cells.
Subject(s)
Central Nervous System/metabolism , Promyelocytic Leukemia Protein/metabolism , Animals , Cell Differentiation/genetics , Cell Differentiation/physiology , Cell Movement/physiology , Cells, Cultured , Central Nervous System/cytology , Glioblastoma/metabolism , Histone-Lysine N-Methyltransferase/metabolism , Humans , Mice , Neurogenesis/genetics , Neurogenesis/physiology , Nuclear Lamina/metabolismABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with <5% survivors after 5 years. High expression levels of ADAM8, a metalloprotease disintegrin, are correlated with poor clinical outcome. We show that ADAM8 expression is associated with increased migration and invasiveness of PDAC cells caused by activation of ERK1/2 and higher MMP activities. For biological function, ADAM8 requires multimerization and associates with ß1 integrin on the cell surface. A peptidomimetic ADAM8 inhibitor, BK-1361, designed by structural modelling of the disintegrin domain, prevents ADAM8 multimerization. In PDAC cells, BK-1361 affects ADAM8 function leading to reduced invasiveness, and less ERK1/2 and MMP activation. BK-1361 application in mice decreased tumour burden and metastasis of implanted pancreatic tumour cells and provides improved metrics of clinical symptoms and survival in a Kras(G12D)-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy.
Subject(s)
ADAM Proteins/metabolism , Membrane Proteins/metabolism , Molecular Targeted Therapy , Pancreatic Neoplasms/drug therapy , ADAM Proteins/antagonists & inhibitors , Animals , Blotting, Western , Carcinoma, Pancreatic Ductal/enzymology , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Cell Movement/drug effects , Extracellular Space/metabolism , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Gene Knockdown Techniques , Humans , Hydroxamic Acids/pharmacology , Hydroxamic Acids/therapeutic use , Integrin beta1/metabolism , Kaplan-Meier Estimate , Matrix Metalloproteinase 14/metabolism , Matrix Metalloproteinase 2/metabolism , Membrane Proteins/antagonists & inhibitors , Mice , Neoplasm Invasiveness , Pancreatic Neoplasms/enzymology , Pancreatic Neoplasms/pathology , Peptides, Cyclic/pharmacology , Peptides, Cyclic/therapeutic use , Phosphorylation/drug effects , Protein Binding/drug effects , Protein Multimerization/drug effects , Protein Processing, Post-Translational , Signal Transduction/drug effectsABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer with poor prognosis. Despite extensive efforts, the current treatment methods have limited success. Therefore, novel therapeutic approaches are required. The pancreatic tumor microenvironment is rich in growth factors and inflammatory cytokines that support tumor growth, and it is highly immunosuppressive. Up-regulation of cytokine pathways has been shown to modulate PDAC progression and immune evasion; therefore targeting cytokines may have therapeutic benefits. In this review we provide an overview of current understanding of pro- and anti-inflammatory cytokines in pancreatic cancer and their potential as therapeutic targets.
Subject(s)
Carcinoma, Pancreatic Ductal/etiology , Cytokines/metabolism , Inflammation Mediators/metabolism , Inflammation/complications , Pancreatic Neoplasms/etiology , Animals , Anti-Inflammatory Agents/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/metabolism , Cytokines/antagonists & inhibitors , Humans , Inflammation/drug therapy , Inflammation/immunology , Inflammation/metabolism , Inflammation Mediators/antagonists & inhibitors , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/metabolism , Signal Transduction , Tumor Escape , Tumor MicroenvironmentABSTRACT
NSCLC remains one of the most challenging malignancies to treat. Despite the introduction of innovative therapies over the last decade, the 5-year survival of NSCLC is still <20%. Clearly, novel, therapeutic approaches are required. Targeting the immune system to derive meaningful clinical benefit has proved successful in various malignancies in recent years. As a result, there is renewed focus on the use of immunotherapy in lung cancer. In this review, we provide an overview of current immune-modulatory approaches in the treatment of NSCLC.
