The genome analyses identified driver genes for gastric and colorectal cancer. We have constructed novel mouse models and tumor-derived organoid transplantation models to examine the mechanisms of development and metastasis of gastrointestinal cancers.
Most p53 mutations in cancer are missense-type, resulting in oncogenic mutant p53 protein, known as gain-of-function (GOF) mutation. We have introduced R270H GOF mutant p53 in ApcΔ716 intestinal tumor model, and identified that loss of wild-type p53 by LOH in addition to GOF mutation accelerates liver metastasis through increased survival and clonal expansion (Nakayama M, et al, Nat Commun, 2020).
In the concept of polyclonal metastasis, cell clusters are detached from the primary site and develops genetically heterogenous metastatic lesions. Using the mouse intestinal tumor-derived organoids, we found that malignant metastatic cells can generate fibrotic niche in the liver, which support survival and proliferation of non-metastatic cells within the same clusters and develop polyclonal metastasis (Kok SY, Oshima H, et al, Nat Com Commun, 2020).
Using the high speed (HS)-scanning ion conductance microscope (SICM), we have analyzed cell surface topography and physical properties including stiffness of intestinal tumor-derived organoids, and identified metastatic cell-specific mechanical characteristics (Wang D, et al, in preparation).
Heterozygous p53 GOF mutation induces submucosal invasion, and additional loss of wild-type p53 by LOH causes increased cell survival and clonal proliferation, which further accelerates metastasis.
(modified from Nakayama M, et al, Nat Commun, 2020)
When metastatic AKTP and non-metastatic AP cells are co-disseminated to the liver, AKTP cells induce fibrotic niche generation, which support survival and proliferation of AP cells, leading to polyclonal metastasis.
(modified from Kok SY, Oshima H, Nat Commun, 2020)