Journal Article

Metastatic phenotype and immunosuppressive tumour microenvironment in pancreatic ductal adenocarcinoma: Key role of the urokinase plasminogen activator (PLAU)

Uddin, Md. Nazim, Moni, Mohammad Ali, Pirola, Ron, Notta, Faiyaz, Apte, Minoti, Buckley, Benjamin J., Hosen, S. M. Zahid, Perera, Chamini, Xu, Zhihong, Mekapogu, Alpha Raj, Wilson, Jeremy, Gallinger, Steven, Pang, Tony C. Y., Ranson, Marie, Goldstein, David

2022

Overview

Previous studies have revealed the role of dysregulated urokinase plasminogen activator (encoded by ) expression and activity in several pathways associated with cancer progression. However, systematic investigation into the association of expression with factors that modulate PDAC (pancreatic ductal adenocarcinoma) progression is lacking, such as those affecting stromal (pancreatic stellate cell, PSC)-cancer cell interactions, tumour immunity, PDAC subtypes and clinical outcomes from potential inhibition. This study used an integrated bioinformatics approach to identify prognostic markers correlated with PLAU expression using different transcriptomics, proteomics, and clinical data sets. We then determined the association of dysregulated and correlated signatures with oncogenic pathways, metastatic phenotypes, stroma, immunosuppressive tumour microenvironment (TME) and clinical outcome. Finally, using an orthotopic model of pancreatic cancer, we confirmed the predicted effect of inhibiting PLAU on tumour growth and metastasis. Our analyses revealed that upregulation is not only associated with numerous other prognostic markers but also associated with the activation of various oncogenic signalling pathways, aggressive phenotypes relevant to PDAC growth and metastasis, such as proliferation, epithelial-mesenchymal transition (EMT), stemness, hypoxia, extracellular cell matrix (ECM) degradation, upregulation of stromal signatures, and immune suppression in the tumour microenvironment (TME). Moreover, the upregulation of was directly connected with signalling pathways known to mediate PSC-cancer cell interactions. Furthermore, upregulation was associated with the aggressive basal/squamous phenotype of PDAC and significantly reduced overall survival, indicating that this subset of patients may benefit from therapeutic interventions to inhibit activity. Our studies with a clinically relevant orthotopic pancreatic model showed that even short-term PLAU inhibition is sufficient to significantly halt tumour growth and, importantly, eliminate visible metastasis. Elevated correlates with increased aggressive phenotypes, stromal score, and immune suppression in PDAC. upregulation is also closely associated with the basal subtype type of PDAC; patients with this subtype are at high risk of mortality from the disease and may benefit from therapeutic targeting of .

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Adenocarcinoma / Bioinformatics / Cancer therapies / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - metabolism / Carcinoma, Pancreatic Ductal - secondary / Cell interactions / Cytokines / ECM degradation / EMT / Extracellular matrix / Gene expression / Genomes / Growth factors / Humans / Hypoxia / Immunology / Kinases / Medical prognosis / Metastases / Metastasis / Pancreatic cancer / Pancreatic Neoplasms / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - pathology / pancreatic stellate cells / Phenotype / Phenotypes / PLAU / proliferation / Protein expression / Proteins / Proteomics / Signal transduction / stemness / Stroma / Survival analysis / Therapeutic applications / Therapeutic targets / Transcription factors / Transcriptomics / Tumor microenvironment / Tumor Microenvironment - genetics / Tumors / U-Plasminogen activator / Up-regulation / Urokinase-Type Plasminogen Activator - genetics