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Nat Commun. 2019 Aug 12;10(1):3637. doi: 10.1038/s41467-019-10968-6.

CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan.

Author information

1
The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia.
2
St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, 2010, Australia.
3
Molecular Pathology department, the Netherlands Cancer Institute, Amsterdam, 1066CX, the Netherlands.
4
Graduate school of Biomedical Engineering, University of New South Wales Sydney, Sydney, NSW, 2052, Australia.
5
Cancer Research UK Beatson Institute, Glasgow Scotland, G61 BD, UK.
6
Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, VIC, 3086, Australia.
7
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
8
Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, CA, 92121, USA.
9
Children's Medical Research Institute, University of Sydney, Sydney, NSW, 2006, Australia.
10
Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, 9054, New Zealand.
11
Maurice Wilkins Centre, University of Otago, Dunedin, 9054, New Zealand.
12
Biomedical imaging facility, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
13
Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
14
Australian Centre for Nanomedicine, University of New South Wales, Sydney, NSW, 2052, Australia.
15
Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.
16
NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, NSW, 2065, Australia.
17
Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, 2065, Australia.
18
Schools of Life and Environmental Sciences, the Charles Perkin Centre, the University of Sydney, Sydney, NSW, 2006, Australia.
19
The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. t.cox@garvan.org.au.
20
St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, 2010, Australia. t.cox@garvan.org.au.
21
The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. p.timpson@garvan.org.au.
22
St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, 2010, Australia. p.timpson@garvan.org.au.

Abstract

Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.

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