Modelling cancer mutations using CRISPR/Cas9 genome editing

Lannagan TRM1, Lee YK1, Wang T1, Roper J2, Bettington M3,4, Fennell L4, Vrbanac L1, Jonavicius L5, Somashekar R1, Gieniec K1, Yang M1, Ng JQ1, Suzuki N1, Ichinose M1, Wright JA1, Kobayashi H1, Putoczki TL6, Abud HE7, Marker J8, Kleve S5, Wirapati A9, Tejpar S10, Leggett BA4, Whitehall VL4, Worthley DL1 and Woods SL1

  1. School of Medicine, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, SA Australia.
  2. Tufts Medical Center & Tufts University, School of Medicine, Boston, MA USA.
  3. Envoi Specialist Pathologists, Brisbane, QLD Australia.
  4. QIMR Berghofer Medical Research Institute, Brisbane, QLD Australia.
  5. Department of Anatomical Pathology, Flinders Medical Centre, Bedford Park, SA Australia. Department of Medical Biology, University of Melbourne and the Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC Australia. Cancer Program, Monash Biomedicine Discovery Institute and the Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia. Cancer Voices SA, Adelaide, South Australia, Australia. Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland. Digestive Oncology Unit, Department of Oncology, University Hospitals Leuven, Leuven, Belgium.

In this age of next generation sequencing we are fast accruing more information on cancer associated genetic alterations than ever before. How do we translate this new knowledge into better outcomes for cancer patients? Clearly we must prioritise genetic alterations for study from this wealth of data. Here we utilise the organoid culture technique, combined with CRISPR/Cas9 genome engineering, to sequentially introduce genetic alterations associated with the serrated pathway to colorectal cancer (CRC). Our novel preclinical models enable therapeutic evaluation in known, complex genetic landscapes. These models can also be readily personalised to investigate the many leads generated by next generation sequencing of our patients.