A team of researchers has revealed some of the mechanisms by which polyps develop into colorectal cancer, setting the framework for improved surveillance for the disease. Their study, published by Chen et al in the journal Cell, describes findings using a single-cell transcriptomic and imaging atlas of the two most common colorectal polyps: conventional adenomas and serrated polyps.
The investigators determined that adenomas arise from expansion of stem cells that are driven by activation of WNT signaling, which contributes to the development of cancer, while serrated polyps derive into cancer through the process of gastric metaplasia. The finding about metaplasia was surprising, the researchers said.
“Cellular plasticity through metaplasia is now recognized as a key pathway in cancer initiation,” said Ken Lau, PhD, Associate Professor of Cell and Developmental Biology at Vanderbilt University School of Medicine and one of the study’s corresponding 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 did an integrative analysis of 128 data sets 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.
The cells from serrated polyps did not exhibit WNT pathway activation nor a stem cell signature. Moreover, the researchers observed 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 highly expressed genes in the serrated-specific cells that are not normally found in the colon but are usually expressed in the stomach, including 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 wrote.
The study provided a number of other findings of clinical significance. For instance, sessile serrated lesions can be challenging to identify, and the study suggested biomarkers that may confirm their diagnosis. The study also revealed much 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, PhD, Research Professor in the Division of Epidemiology at Vanderbilt and a corresponding author of the study.
Disclosure: The research was supported by the Human Tumor Atlas Network grant from the Cancer Moonshot initiative of the National Cancer Institute, and other funding came from the National Cancer Institute, the Congressionally Directed Medical Research Program of the U.S. Department of Defense, Cancer UK, Janssen, and the Nicholas Tierney GI Cancer Memorial Fund. For full disclosures of the study authors, visit cell.com.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.