CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan
Authors: Pauline Mélénec
Mo Ballal
Ray Asghari
Ales Benda
R Scott Mead
David K Chang
Mark Pinese
Judith Dixon
Andrew Da Silva
Thomas J O&#x27;Rourke
Andrew D Clouston
Caroline L Cooper
Jaswinder S Samra
Chris Worthley
Nikolajs Zeps
Vincent W Lam
Venkateswar Addala
Angela Steinmann
Lesley Andrews
Suresh Mathivanan
Kasim Ismail
Amitabha Das
John V Pearson
Krishna P Epari
Allan Spigellman
Rita T Lawlor
Kynan Feeney
Chelsie O&#x27;Connnor
Nan Q Nguyen
Michael Texler
Michael Hatzifotis
Tanya Dwarte
Angelika Christ
Pamela Mukhopadhyay
Anthony W Braithwaite
Nick Pavlakis
Danielle Froio
Andrew R Ruszkiewicz
Phoebe A Phillips
Sanjay Mukhedkar
Monisha Samuel
Duncan McLeod
Anthony J Gill
Aurélie S Cazet
Xanthe Metcalf
David R Fletcher
Stefania Beghelli
Hilda A High
Marina Pajic
Stephen Kazakoff
Benjamin L Parker
David R Croucher
Morghan C Lucas
Christopher L Wolfgang
Daniel Christ
Andrew P Barbour
Kendelle J Murphy
Peter Hodgkinson
Sean C Warren
Claire Vennin
Paul Timpson
Ralph H Hruban
Vincenzo Corbo
Daniel Roden
Jonathan W Fawcett
James G Kench
Claudio Bassi
Nigel B Jamieson
Mehrdad Nikfarjam
Oliver Holmes
Shona Ritchie
Annabel Goodwin
Tim Bruxner
Ashleigh Parkin
Charbel Sandroussi
Nicola Waddell
Peter H Cosman
Judy Kirk
Brooke Pereira
Wilfred Leung
Owen J Sansom
Virginia Papangelis
James R Eshleman
Peter Grimison
Cecilia R Chambers
Darren Pavey
Kellee Slater
Conrad Leonard
John Chen
Anaiis Zaratzian
Mehreen Arshi
Katherine Tucker
Thomas R Cox
Romain Rouet
Katia Nones
Australian Pancreatic Genome Initiative (APGI)
David Herrmann
Amber L Johns
Oliver Hofmann
Andrew V Biankin
Ann-Marie Patch
Scott Wood
Angela Chou
Yingxiao Wang
Gabriella Kalna
Daniel A Reed
Jennifer P Morton
Sean M Grimmond
Lorraine A Chantrill
Neil D Merrett
Shane T Grey
Mark E Brooke-Smith
Maria Beilin
Zehra Elgundi
Max Nobis
Felicity Newell
Maria Scardoni
David Williams
Cindy Forest
John M Whitelock
Alina Stoita
Journal: Nature Communications (2019)
Discipline: Multidisciplinary
Keywords: cancer-associated fibroblasts; pancreatic cancer; p53; gain-of-function mutant; metastasis
Affiliations: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia., St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, 2010, Australia., Molecular Pathology department, the Netherlands Cancer Institute, Amsterdam, 1066CX, the Netherlands., Graduate school of Biomedical Engineering, University of New South Wales Sydney, Sydney, NSW, 2052, Australia., Cancer Research UK Beatson Institute, Glasgow Scotland, G61 BD, UK., Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, VIC, 3086, Australia., Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA., Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, CA, 92121, USA., Children's Medical Research Institute, University of Sydney, Sydney, NSW, 2006, Australia., Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, 9054, New Zealand., Maurice Wilkins Centre, University of Otago, Dunedin, 9054, New Zealand., Biomedical imaging facility, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia., Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia., Australian Centre for Nanomedicine, University of New South Wales, Sydney, NSW, 2052, Australia., Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia., NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, NSW, 2065, Australia., Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, 2065, Australia., Schools of Life and Environmental Sciences, the Charles Perkin Centre, the University of Sydney, Sydney, NSW, 2006, Australia., The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Sydney, NSW, 2010, Australia. ., St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, 2010, Australia. .

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. 

Retracted: No

PubPeer comments:
 Fig 3c panel (iii) single cells is a zoom of Fig 3b panel (mt-e-CAF matrices, p53 staining, 100% fl-CC seeded). , 
 #1 I understood that in 3b they are showing overall invasiveness and in 3c the mode of invasion of the same conditions, so I think it is supposed to be a zoom of Fig3b. , 
 #1 #2 No this is not OK. It is not clearly stated that it is a zoom for one. Second, the 50:50 condition should be used as an example and not a condition with one cell type. That the authors have to resort to showing a zoom questions how many times or in how many replicates these analyses were done. It also questions the data in 3d. ,