Exploring microbiome modulators of colorectal cancer signaling pathways

Colorectal cancer (CRC) constitutes one of the leading causes of cancer-related deaths worldwide, which
typically insidiously develops through a long years-long process involving mutations accumulating in
different genes that are essential to a variety of cellular pathways such as WNT, RAS?MAPK, TGF-?, P53,
and DNA mismatch-repair pathways. The gut microbiome has been suggested to causally impact CRC
development, progression, and response to treatment. However, the mechanisms by which gut microbial
signals impact intestinal epithelial cell signaling and transformation remain elusive. Such causal
understanding of host-microbiome modulatory activity on signaling pathways central to CRC development
and clinical behavior may hold promise in harnessing microbes and their secreted products in preventing and
treating CRC. In this proposed project, we aim to establish a high throughput screening pipeline of live
imaging to quantify the simultaneous changes in the major signaling pathways. This will enable us to
massively screen thousands of microbiome-related, food-related and host-related molecules involved in the
host-microbiome niche and their simultaneous effects on multiple key signaling pathways in human CRC.
Top reproducible hits will then be validated on their effects in mouse and human organoid cultures, and then
in in vivo setting in models of CRC in mice (such as AOM/DSS and Apcmin/+). Together, this in vivo to in
vitro to in vivo approach will help in better understanding the host-microbiome modulatory activity on
signaling pathways central to CRC development and clinical behavior, which may hold promise in
harnessing microbes and their secreted products in preventing CRC.