Lan Zhou, associate professor of pathology at Case Western Reserve University School of Medicine, has received a five-year, $2 million grant from the National Cancer Institute of the National Institutes of Health to study human colorectal cancer. Her work focuses on the effect of the imbalance of the gut microbiome, the immune response, and genetics in the development of adenocarcinoma (cancer that forms in the lining of the glands) through the serrated pathway.

Photo of Lan Zhou

Lan Zhou

The “serrated pathway” is a molecular pathway postulated for a subset of colorectal cancers that develop from certain serrated adenomas/polyps—growths that have a saw-tooth appearance when viewed under the microscope. It is distinct from the conventional adenoma–carcinoma (cancer) pathway, which involves “flat” growths. As many as 15 percent of all colorectal cancers start from serrated adenoma polyps with dysplasia (cells that look distinctively abnormal under the microscope). Serrated lesions are also found in patients with irritable bowel disease and colitis, often contributing to colon cancer development in that population. Serrated cancer lesions are not well described, do not respond well to chemotherapy compared to other tumors, and are associated with worse prognoses.

“Colon cancer can start from different adenomas and have different mechanisms, which is why it is imperative to recognize these variations and apply specific preventive treatment,” said Zhou, who is also a Case Comprehensive Cancer Center member.

Under the grant, Zhou and her team will use a combination of approaches in mouse models and human tissue to study the carcinogenic transformation of colon epithelium (tissue that lines bodily organs) characterized by the loss of HES1, an important signaling molecule that regulates cell homeostasis and the differentiation of stem cells into specialized cells. This process, known as Notch signaling, is crucial for maintaining the balance between cell proliferation, differentiation, and normal cell death.

Zhou’s findings from mouse models strongly support an inflammation- and dysplasia-suppressive function of epithelial Notch/HES1 signaling. But malfunctions may lead to the development and/or progression of colorectal cancer. The investigators aim to determine how this transformation occurs and how it is enhanced by pro-inflammatory activity in the body. Inflammation is a known risk factor for developing many diseases, including colorectal cancer.

The approaches they will draw on include the use of organoid culture (3-D mouse cell aggregates that function like organs); network bioinformatics analysis; assessment of microorganisms such as bacteria by deep gene-sequencing (sequencing a genomic area up to thousands of times to profile the microbial community).

Zhou previously reported that expression of HES1 is lost in 92 percent of serrated pre-cancer lesions (as well as being a prominent feature of irritable bowel disease-associated serrated lesions), whereas its expression in normal colon tissue and in benign polyps remains intact. “Our hypothesis is that HES1-loss disrupts epithelial homeostasis and causes increased inflammation that promotes transformation of serrated adenocarcinoma,” said Zhou. The research team will aim to describe how this process operates both singularly and in interaction with interleukin-1 beta, a protein that initiates and propagates inflammation. Blocking it may prevent or suppress tumor development and progression.

“At the end of this study, we will gain a deeper and broader understanding of the mechanism by which epithelial HES1-loss disrupts epithelial homeostasis and orchestrates a pro-inflammatory and pro-carcinogenic microenvironment,” said Zhou. “We hope our findings will result in more effective and targeted preventive treatments for a subset of colorectal cancer.”

Among cancers affecting both men and women, colorectal cancer is the second leading cause of cancer-related deaths in the United States. It is the third most common cancer in both men and women. Worldwide rates for colorectal cancer are similar. Surgery, combined with chemotherapy, is the conventional treatment, although resistance to chemotherapy is common in advanced cases.

“The high death rate of advanced colorectal cancer is attributable to limited treatment options,” added Zhou. “In the search for better therapeutic options, malfunctioning Notch/HES1 signaling has emerged as a potential target and a potential source of hope for a subgroup of patients with this terrible disease.”