Streamlined Approach Discovered for Treating Bowel Cancer

More than 4,000 Australians die from bowel cancer each year, and more than 17,000 new cases of this cancer will be diagnosed in 2018. Scientists are working to understand the genetic drivers of bowel cancer, with a special interest in those cancers which are the hardest to treat, and which have the poorest prognosis.

A new method helps determine which DNA changes are important to the cancer, in a fraction of the time, at less expense and using fewer animals than traditional genetically-engineered models that are used in cancer research. Analysis of the models, combined with patient data, has suggested potential drug vulnerabilities that are being tested.

An international team of scientists led by those at the University of Adelaide (Adelaide, Australia) have discovered a faster, more cost-effective way to determine which DNA mutations cause human bowel cancer. Serrated colorectal cancer (CRC) accounts for approximately 25% of cases and includes tumors 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 tumor suppressor genes. The team used organoid culture combined with CRISPR/Cas9 genome engineering to sequentially introduce genetic alterations associated with serrated CRC and which regulate the stem cell niche, senescence and DNA mismatch repair.

The scientists reported that targeted biallelic gene alterations were verified by DNA sequencing. Organoid growth in the absence of niche factors was assessed, as well as analysis of downstream molecular pathway activity. Orthotopic engraftment of complex organoid lines, but not BrafV600E alone, quickly generated adenocarcinoma in vivo with serrated features consistent with human disease. Loss of the essential DNA mismatch repair enzyme, MutL Homolog 1(Mlh1), led to microsatellite instability. Sphingolipid metabolism genes are differentially regulated in both our mouse models of serrated CRC and human CRC, with key members of this pathway having prognostic significance in the human setting.

The authors concluded that they had generated rapid, complex models of serrated CRC to determine the contribution of specific genetic alterations to carcinogenesis. Analysis of the models alongside patient data has led to the identification of a potential susceptibility for this tumor type. Susan L. Woods, PhD, a Senior Research Fellow and a study co-leader, said, “Now, we have rapidly made new models of bowel cancer that mimic the complex genetic (DNA) changes that we see in human tumors and recapitulate features of the human disease.” The study was published on April 17, 2018, in the journal GUT.

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