Journal article

Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis

Tamsin RM Lannagan, Young K Lee, Tongtong Wang, Jatin Roper, Mark L Bettington, Lochlan Fennell, Laura Vrbanac, Lisa Jonavicius, Roshini Somashekar, Krystyna Gieniec, Miao Yang, Jia Q Ng, Nobumi Suzuki, Mari Ichinose, Josephine A Wright, Hiroki Kobayashi, Tracey L Putoczki, Yoku Hayakawa, Simon J Leedham, Helen E Abud Show all

GUT | BMJ PUBLISHING GROUP | Published : 2019

Abstract

OBJECTIVE: Serrated colorectal cancer (CRC) accounts for approximately 25% of cases and includes tumours that are among the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen-activated kinase pathway gene, BRAF, and epigenetic modifications termed the CpG Island Methylator Phenotype, leading to epigenetic silencing of key tumour suppressor genes. It is still not clear which (epi-)genetic changes are most important in neoplastic progression and we begin to address this knowledge gap herein. DESIGN: We use organoid culture combined with CRISPR/Cas9 genome engineering to sequentially introduce genetic alterations associated ..

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Grants

Awarded by Cure Cancer Australia/Cancer Australia


Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by National Institutes of Health (NIH)


Awarded by Department of Defense


Awarded by Koch Institute Support Grant from the National Cancer Institute


Awarded by NATIONAL CANCER INSTITUTE


Awarded by NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES


Awarded by NATIONAL INSTITUTE ON AGING


Funding Acknowledgements

This work was supported by Cure Cancer Australia/Cancer Australia (APP1102534), the Cancer Council SA Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health SA, by Pathology Queensland, by the Australian National Health and Medical Research Council (NHMRC) (through APP1081852, APP1140236), by the National Institutes of Health (NIH) (K08 CA198002, R00 AG 045144, R01 CA211184), the Department of Defense (CA120198), the V Foundation V Scholar Award, the Sidney Kimmel Scholar Award, the Pew-Stewart Trust Scholar Award, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund, the American Federation of Aging Research, as well as by the Koch Institute Support Grant P30-CA14051 from the National Cancer Institute. DLW is supported by a NHMRC Career Development Fellowship, VLJW by a Gastroenterological Society of Australia Senior Research Fellowship.