VOON, Dominic Chih Cheng
It has been established that “cancer is a genetic disease”. Hover, it has not yet been fully understood the biological mechanisms of malignant progression by driver mutations. We have constructed mouse models and organoids, and examined phenotypes to understand mechanism for invasion and metastasis of gastrointestinal cancers.
TGF-β signaling plays a tumor suppressor role in colon cancer development. We found that TGF-β suppression together with inflammation causes submucosal colon cancer development (Oshima, et al, Cancer Res, 2015).
Disruption of MyD88 signaling in tumor model mice caused significant suppression of inflammatory environment and tumorigenesis. Thus, innate immunity plays a role in tumorigenesis (Maeda, et al, Cancer Prev Res, 2016).
About 75% of p53 mutations in cancers are missense type. We introduced mutant p53 R270H gene in intestinal tumor mouse model, and found that mutant p53 induces submucosal invasion through activation of transcription factors NF-κB and β-catenin (Nakayama, et al, Oncogene, 2017).
We introduced five driver mutations for colorectal cancer development in mouse intestine, and found that mutations in Apc, Kras, and Tgfbr2 is a minimum core for malignant phenotype in the primary cancer and efficient liver metastasis. (Sakai, et al, Cancer Res, 2018).
Expression of mutant p53 R270H induces nuclear accumulation of p53 and complex glandular organoid structure, which represent malignant phenotype.
Moreover, multiple crossing of driver gene mutant mice revealed combination of mutations for each process of malignancy, including invasion and metastasis.