The role of activin signaling in colorectal cancer EMT induction

2019 Fiscal Year Research-status Report

• Project/Area Number: 19K23882
• Research Institution: Kanazawa University
• Principal Investigator: WANG DONG 金沢大学, ナノ生命科学研究所, 特任助教 (20842983)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Keywords: Activin / EMT / p53 mutation

Outline of Annual Research Achievements

Since Activin shares the same downstream genes as TGFβ, we hypothesized that Activin induces EMT in colorectal cancer, especially in tumors with TGFBR2 mutations. However, the mechanism is not yet elucidated. In this research, Activin treats a series of organoids with multiple gene mutations to confirm Activin’s induction on EMT by the morphological examination, in vivo and in vitro functional studies. RNA-seq and gene expression interference will be used to elucidate the mechanism by which Activin induces EMT and the regulatory relationship between Activin and the mutant genes. Understanding the mechanisms of Activin-induced EMT helps develop new therapeutic strategies.I have confirmed that Activin induces EMT in some organoids, and this process is related to the mutations of p53.

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

To verify our hypothesis, we use Activin to treat a series of organoids with distinct gene mutations and find that Activin induces EMT phenotype. And Activin could not induce EMT any more after Activin receptor knockout, which confirms that it’s Activin induced such phenotype changes. To figure out which key drive gene mutation works important role in this process, we compared the genotypes between EMT organoids and non-EMT organoids. It shows that the organoids with p53 mutations show EMT phenotype after Activin treatment, which indicates p53 mutation is very important for Activin-induced EMT. To confirm this, the wt-p53 was overexpressed in p53-mutated organoids and hopefully, wt-p53 inhibits Activin-induced EMT. The mechanism that how p53 mutation cooperates Activin is in progress.

Strategy for Future Research Activity

Now, we already send the samples to do RNA-seq. The next step, by analyzing the RNA-seq data, we could know the potential mechanism that how p53 mutation cooperates with Activin to induce EMT. Then, we will confirm the mechanism by disrupting the signal pathway.
Moreover, we are going to try to see the liver metastatic phenotype using Activin treated EMT-induced ouganoids by injection to the spleen of NSG mice.
We try to submit the manuscript about our finding.