Chicago City Wire

In an effort to catalyze more cancer research projects among Illinois faculty and build bridges among diverse disciplines, the Cancer Center at Illinois (CCIL) inaugurated the JumpStart Program in 2022, providing up to $25,000 in research support funds to researchers. This initial cohort includes three researchers: Wenyan Mei, professor of comparative biosciences, Ruby Mendenhall, professor of sociology, and Jonathan Sweedler, professor of chemistry.

We recently sat down with Wenyan Mei to discuss her cancer research and experience as a CCIL member.

Can you tell us a bit about your work?

I am an assistant professor in comparative biosciences in the College of Veterinary Medicine. I employ zebrafish and mouse models to understand how reciprocal interactions between gut microbiota and the host impact host health. I also study how intestinal stem cells are controlled to maintain intestinal epithelial regeneration and prevent colorectal cancer.

What sparked your interest in the JumpStart program?

In the animal model I was working on, I noticed a colorectal cancer phenotype. I thought, “Oh, that looks interesting; I want to dig deeper.” I talked to Rohit (Bhargava) and other leaders to see if they could support me in studying this endeavor. I am grateful that they wanted to support me and further this research. I was nominated to be a participant in the program and received JumpStart funding in Fall 2022.

What were the expectations as a JumpStart program participant?

This program is intended to help faculty members who are not used to working in cancer research. As a CCIL member and program participant, I am: 1) establishing a research model that can be used for cancer research, 2) engaging in collaboration with other researchers, and 3) setting up part of our lab for devoted cancer research.

Can you tell us about your cancer research project?

The main discovery of my lab’s work is that a RNA-binding protein named PTBP1 controls intestinal epithelial regeneration through post-transcriptionally regulating gene function. The results of this research were just published in the journal Nucleic Acids Research.

We discovered that PTBP1 executes this role through two mechanisms. First, PTBP1 maintains intestinal stem cell survival by controlling the intestinal stem cell niche. Of particular interest is that PTBP1 controls the expression of a gene called Phlda3 in Paneth cells which are known as niche providers. Paneth cells provide niche support to stem cells and can reacquire intestinal stem cell properties and contribute to intestinal epithelial regeneration upon the loss of intestinal stem cells. We found that deletion of PTBP1 not only disrupts intestinal stem cell niche but also the capacity of the Paneth cell to reacquire stemness. As such, intestinal epithelial regeneration fails in mice with PTBP1 deletion. In addition, we found PTBP1 inhibits its paralog PTBP2 expression in intestinal stem cells by controlling the splicing of PTBP2. Because PTBP2 promotes the splicing program required for neuronal cell differentiation, inhibiting PTBP2 prevents the aberrant differentiation of intestinal stem cells and consequently maintains their stemness. These findings reveal important post-transcriptional regulatory mechanisms through which RNA-binding proteins control stem cell function and tissue regeneration, which helps our future studies on cancer stem cell biology and tumor plasticity.

Following the discoveries of this research project, our lab is generating a new knockout mouse model to delete PTBP1 in Paneth cells, the niche provider, which will allow us to further investigate how PTBP1 controls Paneth cell niche function and stemness through post-transcriptionally regulating gene function. Such studies will help to understand how somatic cells regain stem cell properties under certain conditions for tissue regeneration and tumor development. Our team will once again collaborate with Auinash Kalsotra for this project.

Secondly, our lab is studying how humans develop immune tolerance to gut commensal microbes during infancy and how disruption of this process affects the microbiota composition and increases the susceptibility to diseases such as inflammatory bowel diseases and colorectal cancer. Our recent studies indicated that in addition to controlling intestinal stem cell niche in adulthood, PTBP1 is required for developing intestinal immune tolerance to gut commensal microbes at the neonatal stage. Deleting PTBP1 in the neonatal stage causes IBD and colorectal cancer, and altered gut microbiota composition. Using the PTBP1 knockout mouse model, our lab identified microbial families that are aberrantly high in cancer mice. We are now studying whether and how such microbes alter intestinal stem cell function and induce colorectal cancer. For this project, our lab is collaborating with Shulei Wang,  professor of statistics, whose team helped us to use computational analysis to identify microbiota composition changes in our cancer mice.

Thirdly, our lab will study the beneficials effect of prebiotics and probiotics on treating IBD and colorectal cancer.

For this project, our lab is collaborating with Isaac Cann, professor of animal sciences, to study how some microbes protect humans from diseases by degrading dietary fiber and releasing beneficial compounds.

Assisting in Mei’s JumpStart-funded, published research were two scientists. First, CCIL member Auinash Kalsotra, professor of biochemistry, led a team who did the computational analysis (revealing the post-transcriptional gene changes in PTBP1 knockout mice). Secondly, Jing Yang, professor of comparative biosciences, led a team who the in vitro analysis (revealing the mechanism through which PTBP1 regulates Phlda3 expression).

What are your goals for the future of your cancer research?

With this new discovery in our published paper, I want to dig a little deeper. We are studying how post-transcriptional regulation affects stem cell niche and how its dysregulation may cause cancer development.

I hope to continue cancer research collaboration with other CCIL faculty members and establish my new model systems and acquire the data necessary to apply for NIH funding. For example, to study the role of some anaerobic microbes in driving colorectal cancer development, we are seeking collaboration with bioengineering labs to develop devices that allow the coculture of mammalian tissue cells and anaerobic microbes which require different oxygen conditions.

What would you say to Illinois researchers to encourage them to consider the CCIL JumpStart program?

The funds will help to jump start your cancer research. The interdisciplinary collaboration will be helpful to get you into the field of cancer research because there are many experts here on campus. Also, participating in the CCIL program seminars will be helpful for understanding what’s happening in various fields of cancer research.

Original source can be found here.