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

Autor:	Hosen SMZ; Pancreatic Research Group, SWS Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia., Uddin MN; Institute of Food Science and Technology, Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhaka, Bangladesh., Xu Z; Pancreatic Research Group, SWS Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia., Buckley BJ; Molecular Horizons and School of Chemistry & Molecular Bioscience, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia.; Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia., Perera C; Pancreatic Research Group, SWS Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia., Pang TCY; Pancreatic Research Group, SWS Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.; Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, The University of Sydney, Sydney, NSW, Australia., Mekapogu AR; Pancreatic Research Group, SWS Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia., Moni MA; School of Health and Rehabilitation Sciences, Faculty of Health and Behavioural Sciences, The University of Queensland, St Lucia, QLD, Australia., Notta F; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada., Gallinger S; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada., Pirola R; Pancreatic Research Group, SWS Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia., Wilson J; Pancreatic Research Group, SWS Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia., Ranson M; Molecular Horizons and School of Chemistry & Molecular Bioscience, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia.; Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia., Goldstein D; Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.; Department of Medical Oncology, Prince of Wales Hospital, Randwick, NSW, Australia., Apte M; Pancreatic Research Group, SWS Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Dec 14; Vol. 13, pp. 1060957. Date of Electronic Publication: 2022 Dec 14 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.1060957
Abstrakt:	Background: Previous studies have revealed the role of dysregulated urokinase plasminogen activator (encoded by PLAU ) expression and activity in several pathways associated with cancer progression. However, systematic investigation into the association of PLAU 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 PLAU inhibition. Methods: 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 PLAU and correlated signatures with oncogenic pathways, metastatic phenotypes, stroma, immunosuppressive tumour microenvironment (TME) and clinical outcome. Finally, using an in vivo orthotopic model of pancreatic cancer, we confirmed the predicted effect of inhibiting PLAU on tumour growth and metastasis. Results: Our analyses revealed that PLAU 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 PLAU was directly connected with signalling pathways known to mediate PSC-cancer cell interactions. Furthermore, PLAU 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 PLAU 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. Conclusion: Elevated PLAU correlates with increased aggressive phenotypes, stromal score, and immune suppression in PDAC. PLAU 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 PLAU . Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Hosen, Uddin, Xu, Buckley, Perera, Pang, Mekapogu, Moni, Notta, Gallinger, Pirola, Wilson, Ranson, Goldstein and Apte.)
Databáze:	MEDLINE
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