Matthew Read1,2, David Liu1,2, Cuong P Duong1,3, Carleen Cullinane1,2, William K Murray4, Christina M Fennell1,2, Jake Shortt2,5,6, David Westerman4,7, Paul Burton8,9, Nicholas J Clemons1,2,10, Wayne A Phillips11,12,13,14. 1. Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. 2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. 3. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. 4. Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia. 5. School of Clinical Sciences at Monash Health, Melbourne, Australia. 6. Faculty of Medicine, Nursing & Health Sciences, Monash University, Melbourne, Australia. 7. University of Melbourne, Melbourne, Australia. 8. Monash University Centre for Obesity Research and Education, Alfred Hospital, Melbourne, Australia. 9. Cabrini Hospital, Melbourne, VIC, Australia. 10. Department of Surgery (St. Vincent's Hospital), University of Melbourne, Melbourne, VIC, Australia. 11. Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. wayne.phillips@petermac.org. 12. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. wayne.phillips@petermac.org. 13. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. wayne.phillips@petermac.org. 14. Department of Surgery (St. Vincent's Hospital), University of Melbourne, Melbourne, VIC, Australia. wayne.phillips@petermac.org.
Abstract
BACKGROUND: Recently, there has been an increase in the availability of targeted molecular therapies for cancer treatment. The application of these approaches to esophageal cancer, however, has been hampered by the relative lack of appropriate models for preclinical testing. Patient-derived tumor xenograft (PDTX) models are gaining popularity for studying many cancers. Unfortunately, it has proven difficult to generate xenografts from esophageal cancer using these models. The purpose of this study was to improve the engraftment efficiency of esophageal PDTXs. METHODS: Fresh pieces of esophageal tumors obtained from endoscopic biopsies or resected specimens were collected from 23 patients. The tumors were then coated in Matrigel and transplanted in immunocompromised mice subcutaneously (n = 6) and/or using a novel implantation technique whereby the tumor is placed in a dorsal intramuscular pocket (n = 18). They are then monitored for engraftment. RESULTS: With the novel intramuscular technique, successful engraftment was achieved for all 18 patient tumors. Among these PDTXs, 13 recapitulated the original patient tumors with respect to degree of differentiation, molecular and genetic profiles, and chemotherapeutic response. Lymphomatous transformation was observed in the other five PDTXs. Successful engraftment was achieved for only one of six patient tumors using the classic subcutaneous approach. DISCUSSION: We achieved a much higher engraftment rate of PDTXs using our novel intramuscular transplant technique than has been reported in other published studies. It is hoped that this advancement will help expedite the development and testing of new therapies for esophageal cancer.
BACKGROUND: Recently, there has been an increase in the availability of targeted molecular therapies for cancer treatment. The application of these approaches to esophageal cancer, however, has been hampered by the relative lack of appropriate models for preclinical testing. Patient-derived tumor xenograft (PDTX) models are gaining popularity for studying many cancers. Unfortunately, it has proven difficult to generate xenografts from esophageal cancer using these models. The purpose of this study was to improve the engraftment efficiency of esophageal PDTXs. METHODS: Fresh pieces of esophageal tumors obtained from endoscopic biopsies or resected specimens were collected from 23 patients. The tumors were then coated in Matrigel and transplanted in immunocompromised mice subcutaneously (n = 6) and/or using a novel implantation technique whereby the tumor is placed in a dorsal intramuscular pocket (n = 18). They are then monitored for engraftment. RESULTS: With the novel intramuscular technique, successful engraftment was achieved for all 18 patienttumors. Among these PDTXs, 13 recapitulated the original patienttumors with respect to degree of differentiation, molecular and genetic profiles, and chemotherapeutic response. Lymphomatous transformation was observed in the other five PDTXs. Successful engraftment was achieved for only one of six patienttumors using the classic subcutaneous approach. DISCUSSION: We achieved a much higher engraftment rate of PDTXs using our novel intramuscular transplant technique than has been reported in other published studies. It is hoped that this advancement will help expedite the development and testing of new therapies for esophageal cancer.
Authors: Kathryn Alsop; Heather Thorne; Shahneen Sandhu; Anne Hamilton; Christopher Mintoff; Elizabeth Christie; Odette Spruyt; Scott Williams; Orla McNally; Linda Mileshkin; Sumitra Ananda; Julene Hallo; Sherene Loi; Clare Scott; Peter Savas; Lisa Devereux; Patricia O'Brien; Sameera Gunawardena; Clare Hampson; Kate Strachan; Rufaro Diana Jaravaza; Victoria Francis; Gregory Young; David Ranson; Ravindra Samaranayake; David Stevens; Samantha Boyle; Clare Fedele; Monique Topp; Gwo Ho; Zhi Ling Teo; Renea A Taylor; Melissa M Papargiris; Mitchell G Lawrence; Hong Wang; Gail P Risbridger; Nicole M Haynes; Mikolaj Medon; Ricky W Johnstone; Eva Vidacs; Gisela Mir Arnau; Ismael A Vergara; Anthony T Papenfuss; Grant McArthur; Paul Waring; Shirley Carvosso; Christopher Angel; David Gyorki; Benjamin Solomon; Gillian Mitchell; Sue Shanley; Prudence A Francis; Sarah-Jane Dawson; Amy Haffenden; Erin Tidball; Mila Volchek; Jan Pyman; Mohammed Madadin; Jodie Leditschke; Stephen Cordner; Mark Shackleton; David D Bowtell Journal: Nat Biotechnol Date: 2016-09-12 Impact factor: 54.908
Authors: David S Liu; Cuong P Duong; Sue Haupt; Karen G Montgomery; Colin M House; Walid J Azar; Helen B Pearson; Oliver M Fisher; Matthew Read; Glen R Guerra; Ygal Haupt; Carleen Cullinane; Klas G Wiman; Lars Abrahmsen; Wayne A Phillips; Nicholas J Clemons Journal: Nat Commun Date: 2017-03-28 Impact factor: 14.919
Authors: Alvin Kamili; Andrew J Gifford; Nancy Li; Chelsea Mayoh; Shu-Oi Chow; Timothy W Failes; Georgina L Eden; Roxanne Cadiz; Jinhan Xie; Robyn E Lukeis; Murray D Norris; Michelle Haber; Geoffrey B McCowage; Greg M Arndt; Toby N Trahair; Jamie I Fletcher Journal: Br J Cancer Date: 2020-01-10 Impact factor: 7.640
Authors: Alexander G Heriot; Robert G Ramsay; Wayne A Phillips; Glen R Guerra; Joseph C Kong; Rosemary M Millen; Matthew Read; David S Liu; Sara Roth; Shienny Sampurno; Joseph Sia; Maria-Pia Bernardi; Timothy J Chittleborough; Corina C Behrenbruch; Jiasian Teh; Huiling Xu; Nicole M Haynes; Jiaan Yu; Richard Lupat; David Hawkes; Natasha Di Costanzo; Richard W Tothill; Catherine Mitchell; Samuel Y Ngan Journal: Cell Death Dis Date: 2021-10-18 Impact factor: 8.469
Authors: Shulin Li; Sanne J M Hoefnagel; Matthew Read; Sybren Meijer; Mark I van Berge Henegouwen; Suzanne S Gisbertz; Elena Bonora; David S H Liu; Wayne A Phillips; Silvia Calpe; Ana C P Correia; Maria D C Sancho-Serra; Sandro Mattioli; Kausilia K Krishnadath Journal: Cell Oncol (Dordr) Date: 2022-07-28 Impact factor: 7.051