CCA Travel Grant / Mark Dings visits Broad Institute to decipher mechanisms of metastases

In the lab of Dr. Maarten Bijlsma, Mark’s research focuses on metastases in the abdominal cavity (also called peritoneal metastases). Better understanding of the necessary properties for peritoneal metastasis can contribute to the development of new therapies, such as inhibitors that can block metastatic mechanisms. At Amsterdam UMC – Cancer Center Amsterdam, we discovered that a specific subgroup of patients with colorectal cancer (CRC) are prone to develop peritoneal metastases.¹ In a mouse experiment that followed, we found that the same CRC subtype of cell lines could grow in the abdominal cavity.

Unraveling metastatic disease

The research group of Prof. Todd Golub at The Broad Institute of Harvard and MIT has developed a method over the past years to group cell lines together in a pool by giving each cell line a DNA barcode and quantifying the cell line in numbers through DNA sequencing.²

This method has been applied in research on new cancer drugs. So far, one pool can consist of 500 different cell lines, which means that information for 500 cell lines is generated within one experiment. In 2020, they extended this method and injected these barcoded cell pools into mice.³ After the mice were injected, they looked at which particular cell lines metastasized and found refuge in specific organs. This became the first-generation metastasis map, also known as MetMap.

What the Golub lab had not yet examined were peritoneal metastases. Therefore, I started a collaboration to map the cell lines that can grow in the abdominal cavity using their unique cell pools and barcode method. I contacted Prof. Todd Golub and Dr. Dean Procter and asked if it would be a good idea to combine our expertise and if I could come visit. After about a year of contact, it was finally time, and I was welcome to visit and conduct the experiments myself.

Broad experience in Boston

Prior to the trip to the United States, there were several things that needed to be arranged, such as the visa and housing. The J-1 visa (for short-term researchers) is relatively easy to obtain if you fall under the exemption rules (which apply when you have traveled to the US within a certain time frame using an ESTA), but finding furnished housing for a short period was a challenge. During the time I was in Boston, this city was the second most expensive city in the US - New York being the most expensive! Fortunately, I was able to find a place before leaving, so I could pack my travelbags with peace of mind.

Early September 2022, I arrived in a summery Boston. It's a big metropolis, but once you're in the city center, many destinations are within walking distance, making it feel quite compact and - what Americans call - “European”. After settling in for a few days and exploring the city, the real work could begin!

The vivarium, where I spent most of my time, is on the twelfth floor, giving you a fantastic view of the Charles River and Boston. That's another reason why it wasn't a hardship to work there for a while.

The Broad Institute is located exactly between the cities of Boston and Cambridge, and is surrounded by Novartis, MIT, and Google. They are all high-rise buildings, giving you the impression that (bio)tech is really booming here. In the Netherlands, science parks have been pushed out of the cities, but here it's all right in the center. On the first day, I was warmly welcomed by the Onboarding Team and then given a tour by my collaborator, Dr. Dean Procter. It was special to finally meet someone in person after a year of contact through online meetings.

In principle, the plan for the three months of research was already set: pooling cells, injecting mice, waiting, collecting and processing tissue, and quantifying barcodes. I didn't have time to get bored, as I also had the opportunity to work with the latest generation of organoid cancer models from the Human Cancer Model Initiative (HCMI) and give two presentations on this project at, among others, the National Institute of Health (NIH).

Deciphering metastasis

At this moment, the conclusions still require validation. However, the work has resulted in the first-generation intraperitoneal metastasis map (IP-MetMap), which reveals a cancer type-dependent pattern of metastasis that mirrors clinical observations: solid tumors from intra-abdominal organs have a greater propensity to form peritoneal metastasis compared to cancer cells from extra-abdominal origins.

However, even within a single cancer type, there is significant heterogeneity in the tendency to form peritoneal metastases. In comparison with the original paper, the IP-MetMap revealed features that were previously unrecognized as drivers of metastasis. This demonstrates the usefulness of the IP-MetMap as a resource to support molecular peritoneal metastasis research and highlights the unique biology that underlies peritoneal metastasis.

Acknowledgements

I want to sincerely thank Cancer Center Amsterdam for providing a travel grant that has made this research possible. I have generated a tremendous amount of scientific data, extended my professional network, made friends, and above all gained an unforgettable experience abroad at a top-notch scientific institute.

For more information, contact Mark Dings.

References

^{1 Lenos KJ, et al., Molecular characterization of colorectal cancer related peritoneal metastatic disease. Nat Commun. 2022 Aug 4;13(1):4443. doi: 10.1038/s41467-022-32198-z. PMID: 35927254; PMCID: PMC9352687.}

^{2 Yu C, et al., High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines. Nat Biotechnol. 2016 Apr;34(4):419-23. doi: 10.1038/nbt.3460. Epub 2016 Feb 29. PMID: 26928769; PMCID: PMC5508574.}

^{3 Jin X, et al., A metastasis map of human cancer cell lines. Nature. 2020 Dec;588(7837):331-336. doi: 10.1038/s41586-020-2969-2. Epub 2020 Dec 9. PMID: 33299191; PMCID: PMC8439149.}

Text by Mark Dings.

_{This article was created for Cancer Center Amsterdam.}