Vanderbilt discovery offers hope for colorectal cancer patients

A team of researchers based at Vanderbilt University (VU) reportedly have revealed some of the mechanisms through which polyps turn into colorectal cancer. The discovery could set the framework for improved surveillance for the type of cancer through the use of precision medicine.

Their study, published December 14 in Cell​​, outlines findings from a single-cell transcriptomic and imaging atlas of the two most common colorectal polyps found in human patients: conventional adenomas and serrated polyps.

Researchers determined adenomas emerge from the expansion of stem cells which are driven by activation of WNT signaling, which contributes to the development of cancer; at the same time, serrated polyps turn into cancer through a different process, gastric metaplasia. According to the research team, the discovery regarding metaplasia (an abnormal change of cells into cells that are non-native to the tissue) was surprising.

“Cellular plasticity through metaplasia is now recognized as a key pathway in cancer initiation, and there were pioneering contributions to this area by investigators here at Vanderbilt​,” said Ken Lau, associate professor of Cell and Developmental Biology and one of the study’s authors. “We now have provided evidence of this process and its downstream consequences in one of the largest single-cell transcriptomic studies of human participants from a single center to date​.”

The researchers conducted an integrative analysis of 128 datasets of tissue samples from 62 tumors. They performed single-cell RNA sequencing, multiplex immunofluorescence, and multiplex immunohistochemistry on the samples, which were collected from diverse sex, racial, and age groups.

According to their findings, cells from serrated polyps did not exhibit WNT pathway activation nor a stem cell signature. The researchers also noted that these cells had highly expressed genes not normally found in the colon, leading them to hypothesize that metaplasia plays a role in how serrated polyps become cancerous. The researchers observed in the serrated-specific cells highly expressed genes that are not normally found in the colon but are expressed in the stomach (such as MUC5AC, AQP5, TACSTD2 (TROP2), TFF2, MUC17, and MSLN).

“We propose a new paradigm in which damage to the proximal colon, possibly from microbiota, initiates a metaplastic cascade that may eventually select for survival/proliferative pathways, such as activating mutations in BRAF​,” the researchers commented in the paper. Bob Chen, a VU graduate student, and Cherie Scurrah, PhD, are the paper’s co-first authors.

Other clinically significant findings in the study include that sessile serrated lesions can be challenging to identify; the document suggests biomarkers that may confirm their diagnosis. The study also revealed information about the mechanisms of sessile-serrated lesions in regulating the tumor immune landscape.

“The findings in our atlas lay the foundation for opening novel strategies for interception of cancer progression, including better surveillance protocols, chemoprevention, and prebiotic and probiotic therapies,​” said Martha Shrubsole, research professor in the Division of Epidemiology and a corresponding author.

The VU research received support from the Human Tumor Atlas Network grant from the Cancer Moonshot initiative of the National Cancer Institute and other funding from the National Cancer Institute, the Congressionally Directed Medical Research Program of the US Department of Defense, Cancer UK, Janssen, and the Nicholas Tierney GI Cancer Memorial Fund.

“This massive effort is only made possible through the close collaboration of a multidisciplinary team, integrating expertise from the Vanderbilt University Basic Sciences, the Vanderbilt University Medical Center Epithelial Biology Center, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center​,” said Robert Coffey Jr., Ingram Professor of Cancer Research, professor of Medicine and Cell and Developmental Biology, and a corresponding author.