ABSTRACT
Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-ß (TGF-ß) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-ß pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/activity. Absence of TAp73 leads to activation of TGF-ß signaling through a SMAD-independent pathway, favoring oncogenic TGF-ß effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-ß signaling. By suggesting TAp73 as a predictive marker for response to TGF-ß inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-ß inhibitors.
Subject(s)
Carcinoma, Pancreatic Ductal/pathology , Nuclear Proteins/metabolism , Pancreatic Neoplasms/pathology , Signal Transduction , Smad Proteins/metabolism , Transforming Growth Factor beta/metabolism , Animals , Biglycan/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/mortality , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Epithelial-Mesenchymal Transition , Humans , Male , Mice , Mice, Knockout , Mice, Nude , Mice, Transgenic , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/genetics , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/mortality , RNA Interference , Signal Transduction/physiology , Survival Rate , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/pharmacology , Tumor Cells, CulturedABSTRACT
Pancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/proliferation by modulating N-cadherin/ß-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain.
Subject(s)
Intercellular Signaling Peptides and Proteins/metabolism , Nerve Tissue Proteins/metabolism , Neurons/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Animals , Axons/drug effects , Axons/metabolism , Cadherins/metabolism , Cell Communication/drug effects , Cell Compartmentation/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Culture Media/pharmacology , Fibroblasts/metabolism , Fibroblasts/pathology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mice, Nude , Models, Biological , Neurons/drug effects , Neurons/metabolism , Pancreatic Neoplasms/genetics , Schwann Cells/drug effects , Schwann Cells/metabolism , Schwann Cells/pathology , Signal Transduction/drug effects , Stromal Cells/drug effects , Stromal Cells/metabolism , Stromal Cells/pathology , Transcriptome/genetics , Tumor Microenvironment/drug effects , Tumor Microenvironment/genetics , beta Catenin/metabolism , Pancreatic NeoplasmsABSTRACT
This paper focuses on the activity spectrum of three dimethylalkyl tertiary amines as potential active molecules and the corresponding ammonium salt-based antifouling (AF) paints. Bioassays (using marine bacteria, microalgae and barnacles) and field tests were combined to assess the AF activity of coatings. Bioassay results demonstrated that the ammonium salt-based paints did not inhibit the growth of microorganisms (except the dimethyldodecylammonium-based coatings) and that the tertiary amines were potent towards bacteria, diatoms, and barnacle larvae at non-toxic concentrations (therapeutic ratio, LC50/EC50, <1). The results from field tests indicated that the ammonium salt-based coatings inhibited the settlement of macrofouling and the dimethylhexadecylammonium-based coatings provided protection against slime in comparison with PVC blank panels. Thus, results from laboratory assays did not fully concur with the AF activity of the paints in the field trial.
