C. Arnold Spek

Academisch Medisch Centrum Universiteit van Amsterdam | AMC · Center for Experimental and Molecular Medicine

Pancreatic adenocarcinoma (PDAC) remains largely refractory to chemotherapeutic treatment regimens and, consequently, has the worst survival rate of all cancers. The low efficacy of current treatments results largely from toxicity-dependent dose limitations and premature cessation of therapy. Recently, targeted delivery approaches that may reduce o...

CCAAT/Enhancer-Binding Protein delta (C/EBPδ) is a transcription factor involved in differentiation and inflammation. While sparsely expressed in adult tissues, aberrant expression of C/EBPδ has been associated with different cancers. Initially, re-expression of C/EBPδ in cell cultures limited tumor cell proliferation, assigning it a tumor suppress...

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor clinical prognosis and unsatisfactory treatment options. We previously found that the transcription factor CCAAT/Enhancer-Binding Protein Delta (C/EBPδ) is lowly expressed in PDAC compared to healthy pancreas duct cells, and that patient survival and lymph node involvement in P...

Neoadjuvant chemoradiotherapy (nCRT) improves outcomes in resectable esophageal adenocarcinoma (EAC), but acquired resistance precludes long-term efficacy. Here, we delineate these resistance mechanisms. RNA sequencing on matched patient samples obtained pre-and post-neoadjuvant treatment reveal that oxidative phosphorylation was the most upregulat...

Pancreatic Ductal Adenocarcinoma (PDAC) is among the most aggressive human cancers and occurs globally at an increasing incidence. Metastases are the primary cause of cancer-related death and, in the majority of cases, PDAC is accompanied by metastatic disease at the time of diagnosis, making it a particularly lethal cancer. Regrettably, to date, n...

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and severe disease characterized by excessive matrix deposition in the lungs. Macrophages play crucial roles in maintaining lung homeostasis but are also central in the pathogenesis of lung diseases like pulmonary fibrosis. Especially, macrophage polarization/activation seems...

Pancreatic cancer is a devastating disease with the worst outcome of any human cancer. Despite significant improvements in cancer treatment in general, little progress has been made in pancreatic cancer (PDAC), resulting in an overall 5-year survival rate of less than 10%. This dismal prognosis can be attributed to the limited clinical efficacy of...

Rationale: Although the cysteine protease cathepsin S has been implicated in the pathogenesis of several inflammatory lung diseases, its role has not been examined in the context of acute respiratory distress syndrome, a condition that still lacks specific and effective pharmacological treatments. Objectives: Characterize the status of cathepsin...

Treatment of pancreatic ductal adenocarcinoma (PDAC), a dismal disease with poor survival rates, is hampered by the high prevalence of chemotherapy resistance. Resistance is accompanied by macrophage infiltration into the tumor microenvironment, and infiltrated macrophages are key players in chemotherapy resistance. In the current manuscript, we id...

CCAAT/enhancer-binding protein delta (C/EBPδ) is a member of the C/EBP family of transcription factors. According to the current paradigm, C/EBPδ potentiates cytokine production and modulates macrophage function thereby enhancing the inflammatory response. Remarkably, however, C/EBPδ deficiency does not consistently lead to a reduction in Lipopolys...

CCAAT/enhancer-binding protein delta (C/EBPδ) is a transcription factor involved in apoptosis and proliferation, which is downregulated in pancreatic ductal adenocarcinoma (PDAC) cells. Loss of nuclear C/EBPδ in PDAC cells is associated with decreased patient survival and pro-tumorigenic properties in vitro. Interestingly however, next to C/EBPδ ex...

Pancreatic ductal adenocarcinoma (PDAC) has the worst survival rate of all cancers. This poor prognosis results from the lack of efficient systemic treatment regimens, demanding high-dose chemotherapy that causes severe side effects. To overcome dose-dependent toxicities, we explored the efficacy of targeted drug delivery using a protease-dependent...

Pancreatic acinar cells have high plasticity and can transdifferentiate into ductal-like cells. This acinar-to-ductal metaplasia (ADM) contributes to tissue maintenance but may also contribute to the premalignant transformation that can eventually progress to pancreatic ductal adenocarcinoma (PDAC). Macrophages are key players in ADM, and macrophag...

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown etiology with minimal treatment options. Repetitive alveolar epithelial injury has been suggested as one of the causative mechanisms of this disease. Type 2 alveolar epithelial cells (AEC2) play a crucial role during fibrosis by functioning as stem cells able to repair epithel...

Background Pancreatic ductal adenocarcinoma (PDAC) is a grim disease with high mortality rates. Increased macrophage influx in PDAC is a common hallmark and associated with poor prognosis. Macrophages have high cellular plasticity, which can differentiate into both anti- and pro-tumorigenic properties. Here, we investigated how naïve (M0) macrophag...

CCAAT/enhancer-binding protein δ (C/EBPδ) is a transcription factor involved in growth arrest and differentiation, which has consequently been suggested to harbor tumor suppressive activities. However, C/EBPδ over-expression correlates with poor prognosis in glioblastoma and promotes genomic instability in cervical cancer, hinting at an oncogenic r...

PurposeTargeting tumor-infiltrating macrophages limits progression and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma (PDAC). Protease-activated receptor (PAR)1 drives monocyte/macrophage recruitment, and stromal ablation of PAR1 limits cancer growth and enhances gemcitabine sensitivity in experimental PDAC. However, the fu...

Background: Pancreatic ductal adenocarcinoma (PDAC) is a disease with high mortality rates. Increased macrophage influx in PDAC is common and associated with poor prognosis. Macrophages are highly plastic cells that can exhibit both anti- and pro-tumorigenic properties. Here, we investigated how naïve (M0) macrophages differ from other macrophages...

Background: Pancreatic ductal adenocarcinoma (PDAC) is a disease with high mortality rates. Increased macrophage influx in PDAC is common and associated with poor prognosis. Macrophages are highly plastic cells that can exhibit both anti- and pro-tumorigenic properties. Here, we investigated how naïve (M0) macrophages differ from other macrophages...

Background: Pancreatic ductal adenocarcinoma (PDAC) is a grim disease with high mortality rates. Increased macrophage influx in PDAC is a common hallmark and associated with poor prognosis. Macrophages have high cellular plasticity, which can differentiate into both anti- and pro-tumorigenic properties. Here, we investigated how naïve (M0) macropha...

Pancreatic cancer is a dismal disorder that is histologically characterized by a dense fibrotic stroma around the tumor cells. As the extracellular matrix comprises the bulk of the stroma, matrix degrading proteases may play an important role in pancreatic cancer. It has been suggested that matrix metalloproteases are key drivers of both tumor grow...

Idiopathic pulmonary fibrosis is a rare, progressive and fatal lung disease which affects approximately 5 million persons worldwide. Although pirfenidone and/or nintedanib treatment improves patients’ wellbeing, the prognosis of IPF remains poor with 5-year mortality rates still ranging from 70 to 80%. The promise of the anti-cancer agent nintedani...

Vorapaxar-dependent protease-activated receptor (PAR)-1 inhibition diminishes diabetic nephropathy in experimental type 1 diabetes. As most patients with diabetic nephropathy suffer from type 2 diabetes, the aim of this study was to investigate whether PAR-1 inhibition also limits diabetic nephropathy in experimental type 2 diabetes. Consequently,...

Hedgehog proteins are pivotal morphogens acting through a canonical pathway involving first activation of ligand binding to Patched followed by alleviation of Smoothened receptor inhibition, leading to activation of Gli transcription factors. Noncanonical Hedgehog signaling remains poorly characterized but is thought to be mainly dependent on Smoot...

Idiopathic pulmonary fibrosis (IPF) is a devastating and eventually fatal diffuse parenchymal lung disorder that largely remains refractory to pharmacological therapies [1]. IPF is characterised by excessive fibroblast proliferation leading to the formation of fibroblast foci secreting extracellular matrix, with subsequent disruption of pulmonary s...

Protease activated receptor 1 (PAR‐1), originally identified as the thrombin receptor on platelets and vascular endothelial cells, is expressed on numerous cells throughout the body. Tumor cells, and cells in the tumor microenvironment like cancer‐associated fibroblasts, macrophages, T cells and endothelial cells, are no exception and PAR‐1 express...

End‐stage renal disease, the final stage of all chronic kidney disorders, is associated with renal fibrosis and inevitably leads to renal failure and death. Transition of tubular epithelial cells (TECs) into mesenchymal fibroblasts constitutes a proposed mechanism underlying the progression of renal fibrosis and here we assessed whether protease‐ac...

CCAAT/enhancer-binding protein delta (CEBPD) is associated with the regulation of apoptosis and cell proliferation and is a candidate tumor suppressor gene. Here, we investigated its role in hepatocellular carcinoma (HCC). We observe that CEBPD mRNA expression is significantly downregulated in HCC tumors as compared with adjacent tissues. Protein l...

Protease activated receptor-1 (PAR1) expression is associated with disease progression and overall survival in a variety of cancers. However, the importance of tumor cell PAR1 in pancreatic ductal adenocarcinomas (PDAC) remains unexplored. Utilizing orthotopic models with wild type and PAR1-targeted PDAC cells, we show that tumor cell PAR1 negative...

[This corrects the article on p. 4512 in vol. 9, PMID: 29118913.].

Background: Pancreatic cancer is a dismal disease with limited treatment options. Importantly, in recent years an oncogenic role of protease-activated receptor 1 (PAR1) emerged in various cancer types, and PAR1 is generally accepted to promote tumor progression. PAR1 depletion in stroma limits cancer growth in an orthotopic pancreatic cancer model,...

Background Twenty years after the onset of diabetes, up to 40% of patients develop diabetic nephropathy. Protease-activated receptor-1 (PAR-1) has recently been shown to aggravate the development of experimental diabetic nephropathy. PAR-1 deficient mice develop less albuminuria and glomerular lesions and PAR-1 stimulation induces proliferation and...

Background Idiopathic pulmonary fibrosis is a devastating fibrotic diffuse parenchymal lung disorder that remains refractory to pharmacological therapies. Therefore, novel treatments are urgently required. CCAAT/enhancer binding protein delta (C/EBPδ) is a transcription factor that mediates critical cellular functions in pathophysiology and which w...

Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. Protease-activated receptor 2 (PAR2) is expressed by different cell types in the lungs and can mediate inflammatory responses. We sought to determine the role of PAR2 during pneumococcal pneumonia. Pneumococcal pneumonia or sepsis was induced in wild-typ...

Background: Protease-activated receptor-1 (PAR-1) potentiates diabetic nephropathy (DN) as evident from reduced kidney injury in diabetic PAR-1 deficient mice. Although thrombin is the prototypical PAR-1 agonist, anticoagulant treatment does not limit DN in experimental animal models suggesting that thrombin is not the endogenous PAR-1 agonist driv...

Introduction: Procoagulant factors promote cancer progression and metastasis. Protein C is involved in hemostasis, inflammation and signal transduction, and has a protective effect on the endothelial barrier. In mice, administration of activated protein C reduced experimental metastasis. We assessed the association between protein C and mortality...

Pancreatic cancer is one of the most lethal solid malignancies with little treatment options. We have recently shown that expression of protease activated receptor (PAR)-1 in the tumor microenvironment drives progression and induces chemoresistance of pancreatic cancer. As thrombin is the prototypical PAR-1 agonist, here we addressed the effect of...

Background The most frequent pathogen that causes bacterial meningitis is the Gram-positive bacterium Streptococcus (S.) pneumoniae. CCAAT/enhancer binding protein δ is a transcription factor that has recently been hypothesized to play a detrimental role in outcome of meningitis caused by S. pneumoniae. Here, we studied the role of C/EBPδ prior to...

Endogenously administered activated protein C ameliorates diabetic nephropathy (DN) in a protease-activated receptor-1 (PAR-1)-dependent manner, suggesting that PAR-1 activation limits the progression of DN. Activation of PAR-1 in fibroblast-like cells, however, induces proliferation and extracellular matrix production, thereby driving fibrotic dis...

Introduction In cancer, tumor progression and metastasis are promoted by prohemostatic activity. Protein C (PC) is involved in hemostasis, inflammation and signal transduction, and has a protective effect on the endothelial barrier. In mice, administration of activated PC reduced experimental metastasis. It is unclear whether PC level is associated...

Idiopathic pulmonary fibrosis (IPF) is a destructive disease in part resulting from premature or mature cellular aging. Protease-activated receptor-1 (PAR-1) recently emerged as a critical component in the context of fibrotic lung diseases. Therefore, we aimed to study the role of macrophages in PAR-1-mediated idiopathic pulmonary fibrosis. The num...

Tuberous sclerosis complex (TSC) is caused by inactivating mutations in either TSC1 or TSC2 and is characterized by uncontrolled mTORC1 activation. Drugs that reduce mTOR activity are only partially successful in the treatment of TSC, suggesting that mTOR-independent pathways play a role in disease development. Here, kinome profiles of wild-type an...

Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease which remains refractory to therapy. Despite increasing evidence that protease activated receptor (PAR)-2 contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed whether PAR-2 deficiency persistently reduces bleomycin-induced pul...

Already since the early 1800s, it has been recognised that malignancies may provoke thromboembolic complications, and indeed cancer patients are at increased risk of developing venous thrombosis. Interestingly, case control studies of deep-vein thrombosis suggested that low-molecular-weight heparin (LMWH) improved survival of cancer patients. This...

The prognosis of bacterial meningitis largely depends on the severity of the inflammatory response. The transcription factor CAAT/enhancer-binding protein δ (C/EBPδ) plays a key role in the regulation of the inflammatory response during bacterial infections. Consequently, we assessed the role of C/EBPδ during experimental meningitis. Wild-type and...

Lipid droplets (LDs) hypertrophy in adipocytes is the main cause of energy metabolic system dysfunction, obesity and its afflictions such as T2D. However, the role of adipocytes in linking energy metabolic disorders with insulin regulation is unknown in humans. Human adipocytes constitutively synthesize and secrete insulin, which is biologically fu...

Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease of unknown aetiology. Compelling evidence suggests that both protease-activated receptor (PAR)-1 and PAR-2 participate in the development of pulmonary fibrosis. Previous studies have shown that bleomycin-induced lung fibrosis is diminished in both PAR-1 and PAR-2 d...

Protease activated receptor (PAR)-1 expression in tumor cells is associated with disease progression and overall survival in a variety of cancers of epithelial origin; however, the importance of PAR-1 in the tumor microenvironment remains unexplored. Utilizing an orthotopic pancreatic cancer model in which tumor cells are PAR-1 positive whereas str...

Protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor that functions as a cell-surface sensor for coagulation factors, and other proteases associated with the tumour microenvironment. Pancreatic cancer cells express high levels of PAR-2 and activation of PAR-2 may induce their proliferation and migration. Interestingly however, PAR-...

Objectives: To assess causality of inflammatory RNA molecules for myocardial infarction (MI) using a Mendelian randomization approach. Methods: Samples were 524 men with a history of MI and 628 controls from the Study of Myocardial Infarction Leiden (SMILE). Macrophage migration inhibitory factor (MIF) G-173C, protein tyrosine phosphatase, non-rec...

Renal ischemia/reperfusion (I/R) injury is the main cause of acute renal failure. The severity of injury is determined by endothelial damage as well as inflammatory and apoptotic processes. The anti-coagulants active site inhibited factor VIIa (ASIS) and activated protein C (APC) are besides their anti-coagulant function also known for their cytopr...

Renal ischemia/reperfusion (I/R) injury is the main cause of acute renal failure. The severity of injury is determined by endothelial damage as well as inflammatory and apoptotic processes. The anticoagulants active site inhibited factor VIIa (ASIS) and activated protein C (APC) are besides their anticoagulant function also known for their cytoprot...

Accumulating evidence shows that protease activated receptor-1 (PAR-1) plays an important role in the development of fibrosis, including lung fibrosis. However, whether PAR-1 also plays a role in the development of skin fibrosis remains elusive. The aim of this study was to determine the role of PAR-1 in the development of skin fibrosis. In order t...

Introduction: Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor that functions as a cell-surface sensor for coagulation factors, as well as other proteases associated with the tumor microenvironment. The activation of PAR-2 has been shown to induce proliferation of many cancer cells whereas it also may induce migration. The role...

Introduction: Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor that functions as a cell-surface sensor for coagulation factors, as well as other proteases associated with the tumor micro-environment. The proteolytic activation of PAR-2 has been shown to be involved in angiogenesis and breast cancer development. Moreover, activa...