The Molecular Origins Of Two Types of Cancer Are Closer Than We Knew

March 20, 2023

A new paper paves the way for better detection and prevention of certain precancerous changes in the esophagus and stomach.

Cancer is caused by many different factors and can develop over many years through a precancerous phase. We do not know whether specific triggers lead to cancer via distinct molecular pathways or whether different triggers can set off common pathways. An answer to this debate might help us with a more joined up approach to the early detection of cancer.

A new paper in the journal Cancer Discovery improves our understanding of the origin and molecular history of two cancers occurring in adjacent organs but with very different triggers. Long term, these findings may help inform a more uniform early detection strategy and uncover targets to prevent the progression of these precancerous lesions. Early detection of cancer, or better yet, precancerous lesions, 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 themselves are molecularly similar. This new study closes the gap in scientists’ understanding of how these cancers develop. The authors now show that the molecular makeup of the lesions that precede these cancers (called intestinal metaplasia) are also highly similar even when we zoom into an individual cell and examine the molecular instructions (RNA) being produced by the cell.

“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.” Prof. Rebecca Fitzgerald, the lead author said.

The paper draws on new data collected from medical patients in the United Kingdom, as well as an analysis of existing patient data collected in the US, China, and Singapore. The study was supported by the Medical Research Council, part of the United Kingdom Research and Innovation organization. It was co-authored by teams led by Prof. Rebecca Fitzgerald, the director of the Early Detection Institute at Cambridge University, and Dr. Karol Nowicki-Osuch, Associate Research Scientist at the Irving Institute for Cancer Dynamics at Columbia University, in collaboration with Dr. Simon Tavaré, founding director of 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 gastric (i.e., stomach) cancer develops from normal stomach cells when triggered by H. pylori infection, whereas esophageal adenocarcinoma is triggered by damage from acid and bile which leads to a precancerous lesion called Barrett’s esophagus. Unlike healthy esophagus lined by cell types similar to skin (squamous cells), Barrett’s contains columnar cells normally found in the stomach and intestine. In a previous study, published in the journal Science in 2021, the authors made a surprising discovery that esophageal adenocarcinoma likely comes from a reprogramming of normal stomach cells to become intestinal. This follow-up study offers further evidence for that paper’s findings.

The authors were surprised to see that the precancerous lesions in both organs are virtually indistinguishable at the level of molecular analysis of single cells. Furthermore, the authors observe that some of the individual cells of these conditions showed cellular mosaicism, a state where the cell contains at the same time features of stomach and intestine. A comparison with molecular features from individual cells collected from cancer samples showed that these mosaic cells are most closely related to cancer. They also noticed that the supporting cells around these pre-cancerous cells, fibroblasts, had changed their activation status to resemble that of a fully formed cancer. These findings suggest that it may be the interplay between cell types that sets the stage for cancer. This paves the way for future research to understand the precise mechanisms underlying progression to cancer.

Dr. Karol Nowicki-Osuch, the author leading the analysis said: “We were surprised to see how similar these conditions are. Even though we used some of the most advanced analysis tools available, the differences between conditions were difficult to find. However, what surprised us most, was that individual cells of these precancerous conditions are molecularly a mixture of two normal cell types – stomach and intestine.”

“We’re hopeful and encouraged that these findings will help us build better models of these diseases to better fight them,” said Lizhe (John) Zhuang, author leading in situ tissue imaging analysis.


Read the press release in Columbia news: