Thanks to over two centuries of biomedical research, a cancer diagnosis carries less foreboding weight than it once did. Yet, even the most treatable cancer types are life-threatening if caught too late. With colorectal cancer (CRC), detection remains a challenge: CRC can start in hard-to-reach parts of the colon, making it more difficult to diagnose or study without resorting to invasive endoscopic procedures.
“There’s also major variation in how CRC arises and responds to treatment in different colonic regions,” said Nick Barker and Maxime Gasnier, respectively a Research Director and Senior Scientist at the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB). “As such, it’s vital to accurately model CRC in these regions, so we can identify diagnostic markers and treatment targets suited to different patients.”
A new discovery by Barker, Gasnier and colleagues could help change that state of affairs. In a recently published paper, the team—comprising researchers from A*STAR IMCB, A*STAR Singapore Immunology Network (A*STAR SIgN), Nanyang Technological University, Singapore, and Nerima General Hospital, Tokyo, Japan—confirmed that specific cell proteins can be used to trace cancer-causing mutations to distinct stem cell populations in different regions of the colon.
At the heart of their study is a simple but powerful idea: cancer often begins in the cells responsible for keeping tissues healthy. Throughout the colon, stem cells sit in tiny pits in the colon lining called crypts, multiplying themselves tirelessly to renew the lining every three to five days. However, this rapid regeneration is a double-edged sword—cancer-causing mutations can turn stem cells into potent seeds of cancer.
Using comparative transcriptomics approaches, the team sifted through the diverse proteins produced by colonic stem cells. They identified two new cell-surface proteins that appear in distinct proportions depending on stem cell location: NOX1, enriched in the caecum; and NPY1R, enriched in the distal colon and rectum.
Working with mouse models and with organoids cultivated from NOX1 and NPY1R-positive stem cells, the team found that cancer-causing mutations in NOX1-positive stem cells caused tumours to form predominantly in the caecum, while mutations in NPY1R-positive stem cells induced more tumours in the rectum.
“The newly identified stem cell markers make it possible, for the first time, to evaluate how CRC is initiated in specific colonic regions,” said Gasnier. “In addition, the ability to switch on CRC formation in mice and organoids allows us to model the very earliest stages of cancer, potentially revealing novel early biomarkers for early disease detection.”
The researchers added that this modelling flexibility also opens up more detailed studies of how CRC progresses to advanced stages. “Such advanced regional models of CRC will be invaluable for deciphering mechanisms of cancer development, identifying additional diagnostic biomarkers and therapeutic targets, and testing new cancer therapies in preclinical settings,” Barker added.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB), A*STAR Infectious Diseases Labs (A*STAR IDL) and A*STAR Singapore Immunology Network (A*STAR SIgN).
