The Molecular Origins of Two Types of Cancer Are Closer Than We Knew
A new paper paves the way for better detection and prevention of certain precancerous changes in the esophagus and stomach.
A new paper in the journal Cancer Discovery offers fresh insight into the origin and molecular makeup of two cancers that occur in adjacent organs but have very different triggers. The findings may help inform a more uniform early detection strategy for these cancers and uncover ways of preventing precancerous lesions from progressing to cancer. Early detection of precancerous lesions and cancer greatly increases patients’ chance of survival.
The paper focuses on precancerous changes connected with gastric adenocarcinoma, a stomach cancer, and esophageal adenocarcinoma, a cancer of the esophagus. Previous international studies had shown that gastric and esophageal adenocarcinomas are molecularly similar. This new study closes the gap in scientists’ understanding of how these cancers develop. The authors—who include Columbia researcher Karol Nowicki-Osuch and Simon Tavaré, founding director of the Irving Institute for Cancer Dynamics—now show that the molecular makeup of the lesions that precede these cancers are also highly similar.
“This study increased our understanding of these diseases. We hope that these findings will lead to better ways of detecting and fighting them,” said Nowicki-Osuch, the author leading the analysis.
“We hope this research will further push the development of a unified diagnostic or proactive screening approach for cancers of the stomach and esophagus, which have such poor outcomes unless diagnosed early,” Rebecca Fitzgerald, the director of the Early Cancer Institute at Cambridge University, and a co-author on the paper, said.
The paper, “Single-cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia,” draws on new data collected from medical patients in the United Kingdom, as well as an analysis of existing patient data collected in the U.S., China, and Singapore. The study was supported by the Medical Research Council, part of the United Kingdom Research and Innovation organization. The paper was also supported by Columbia’s Irving Institute for Cancer Dynamics. It was co-authored by teams led by Professor Fitzgerald, and Karol Nowicki-Osuch, associate research scientist at the Irving Institute for Cancer Dynamics.
Previous international research projects have shown that gastric adenocarcinoma and esophageal adenocarcinomas are molecularly very similar. However, the field was perplexed by why that was the case. It is known that infection with H.pylori bacteria, which cause stomach ulcers, can cause gastric adenocarcinoma to develop. Esophageal adenocarcinoma, on the other hand, is triggered by damage from acid and bile that leads to a precancerous lesion called Barrett’s esophagus. Unlike a healthy esophagus, which is lined by cell types similar to skin cells, Barrett’s esophagus contains cells similar to those normally found in the stomach and intestine. A previous study, published in the journal Science in 2021, whose co-authors include Nowicki-Osuch and Fitzgerald, made a surprising discovery that Barrett’s esophagus comes from reprogramming of normal stomach cells. Importantly, they also showed that all esophageal adenocarcinoma likely come from Barrett’s esophagus. This follow-up study offers further evidence for that paper’s findings.
In this new study, the authors used advanced analysis tools to observe that, at a molecular level, precancerous lesions in both the stomach and esophagus are virtually indistinguishable. The authors observed that each cell of both stomach and esophageal precancerous lesions have features of normal stomach and intestinal cells. This mixed cell states can be called “cellular mosaicism,” a state where the cell simultaneously contains features of both the stomach and the intestine. The study suggests that cells that have features of both types of cells—stomach and intestinal—develop into cancers. The study’s authors also observed that some of the supporting cells around the precancerous lesions resemble the cells surrounding fully formed cancers. Even though the cells of precancerous stages do not yet possess cancer properties, the environment created by the supporting cells is primed for cancer development. These findings pave the way for future research to understand the precise mechanisms underlying progression to cancer.
“We were surprised to see how similar these two precancerous conditions are. However, what surprised us most was that individual cells that make up these precancerous lesions are molecularly a mixture of two normal cell types—stomach and intestine,” Nowicki-Osuch said. “We’re hopeful that the identification of this unique mixed cell state will help us better understand how cancers develop from these cells.”