Soluble Compounds Released by Hypoxic Stroma Confer Invasive Properties to Pancreatic Ductal Adenocarcinoma
Dajia Liu,
Anne Steins,
Remy Klaassen,
Amber P. van der Zalm,
Roel J. Bennink,
Geertjan van Tienhoven,
Marc G. Besselink,
Maarten F. Bijlsma,
Hanneke W. M. van Laarhoven
Affiliations
Dajia Liu
Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands
Anne Steins
Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands
Remy Klaassen
Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands
Amber P. van der Zalm
Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands
Roel J. Bennink
Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands
Geertjan van Tienhoven
Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Marc G. Besselink
Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Maarten F. Bijlsma
Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands
Hanneke W. M. van Laarhoven
Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands
Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and a hypoxic microenvironment. Pancreatic stellate cells (PSC) are activated by hypoxia and promote excessive desmoplasia, further contributing to the development of hypoxia. We aimed to explore how hypoxia and stroma interact to contribute to invasive growth in PDAC. [18F]HX4 PET/CT was found to be a feasible non-invasive method to assess tumor hypoxia in 42 patients and correlated with HIF1α immunohistochemistry in matched surgical specimens. [18F]HX4 uptake and HIF1α were strong prognostic markers for overall survival. Co-culture and medium transfer experiments demonstrated that hypoxic PSCs and their supernatant induce upregulation of mesenchymal markers in tumor cells, and that hypoxia-induced stromal factors drive invasive growth in hypoxic PDACs. Through stepwise selection, stromal MMP10 was identified as the most likely candidate responsible for this. In conclusion, hypoxia-activated PSCs promote the invasiveness of PDAC through paracrine signaling. The identification of PSC-derived MMP10 may provide a lead to develop novel stroma-targeting therapies.
