Many patients with colorectal cancer suffer from metastases in the abdominal cavity, which have a big impact on quality of life. These peritoneal metastases lead to poor survival, as there are no effective treatment options available yet. The team of Oncode Investigator Louis Vermeulen (Amsterdam UMC-Cancer Center Amsterdam) and collaborators have now shown that peritoneal metastases occur almost exclusively in a particular type of colon cancer: CMS4. With their research, published today in Nature Communications, the team is now able to explain why and how this type of colon cancer can metastasize to the peritoneum. The answer lies within the protein Moesin.

Almost 13,000 people in The Netherlands received a diagnosis of colorectal cancer (CRC) in 2021. Colorectal cancer comes in different forms based on its genetic characteristics. In a previous study, the team of Louis Vermeulen contributed to a classification system based on gene expression patterns. Of these consensus molecular subtypes (CMSs), the CMS4 subtype has worse overall and relapse free survival, and often shows resistance to chemotherapeutic agents. This is related to metastases of the CMS4 subtype to the peritoneum, the membrane lining of the abdominal cavity and abdominal organs. The current study shows that peritoneal metastases (PM) occur almost exclusively in the CMS4 subtype of colon cancer.

“Our research also shows why current treatments of CRC tumors with peritoneal metastases are not very effective,” says Prof. Vermeulen. “This subtype is resistant to many forms of therapy because peritoneal metastases follow a different evolutionary developmental pathway than CRC metastases in other organs. Metastases of the CMS4 subtype to the peritoneum resemble the primary tumor, whereas - for example - frequently occurring liver metastases are biologically different from their matching primary tumor.”

The team of researchers showed that the occurrence of peritoneal metastases depends on the expression of the Moesin protein (for membrane-organizing extension spike protein). This protein is involved in the ability of cells to adhere and migrate, two key aspects of metastases. “Moesin was expressed in peritoneal metastases far more than in CRC liver metastases and when we inhibit its expression in a mouse model, we see a reduction in the amount of PM,” explains Dr. Kristiaan Lenos, the first author of the study. “All in all, we can conclude that peritoneal metastasis is its own disease entity if you look at the gene expression profile and biological background. Our study actually identified three distinct subsets of PMs, based on gene expression profiles. This means that specific therapies need to be developed to improve the outcome and quality of life for many colorectal cancer patients.”

While Prof. Vermeulen is paving the way for the development of these targeted therapies, he is also looking further into peritoneal metastases in other types of cancer. Together with his collaborators, he is currently studying whether a similar mechanism underlies peritoneal metastases from primary tumors of pancreatic cancer and stomach cancer.

For more information contact Prof. Louis Vermeulen or read the scientific publication here:

Lenos, K.J. et al. (2022) Molecular characterization of colorectal cancer related peritoneal metastatic disease. Nat. Commun. 13, 4443. https://doi.org/10.1038/s41467-022-32198-z

Image: Cells that express moesin (in red) in membrane protrusions and are capable of peritoneal metastasis.

Researchers involved at Cancer Center Amsterdam – Amsterdam UMC:

Kristiaan J. Lenos

Sander Bach

Leandro Ferreira Moreno

Sanne ten Hoorn

Nina R. Sluiter

Sanne Bootsma

Felipe A. Vieira Braga

Lisanne E. Nijman

Tom van den Bosch

Daniel M. Miedema

Erik van Dijk

Bauke Ylstra

Vivian P. Bastiaenen

Charlotte E. L. Klaver

Maria C. Lecca

Khalid El Makrini

Clara C. Elbers

Mark P. G. Dings

Carel J. M. van Noesel

Jan Paul Medema

Jan Koster

Lianne Koens

Pieter J. Tanis

Maarten F. Bijlsma,

Jurriaan B. Tuynman

Louis Vermeulen

Funding for this work was provided by Oncode Institute, The New York Stem Cell Foundation, grants from the Dutch Cancer Society (KWF), the European Research Council, and ZonMw.

Text by Peter Thijssen - Oncode Institute.