by Rachel Harrison, New York University

Clusters of about a hundred tumor cells labeled with red fluorescence were grown inside a transparent jelly-like structure and surrounded by immune cells called macrophages—labeled in green. Tumor cells on the left are growing under normal culture conditions. Tumor cells on the right were grown in a nutrient- and oxygen-scarce region within the 3MIC. These different environments produced dramatic changes in the metastatic features on these tumor cells: almost no migration in cells from the tumor cluster on the left, while the cluster on the right—grown under poor conditions—produced lots of finger-like streams of migratory cells. Credit: Carmofon Lab/NYU

Scientists have created a 3D-printed model to mimic the specific conditions that spur the spread of cancer cells. The model, published in the journal Life Science Alliance, allows researchers to study a process previously hidden from view and may open the door to new screening and treatment options for cancers at risk of spreading.

Thanks to advances in prevention, diagnosis, and treatment, many cancer patients have good prognoses and are living longer. However, some tumors still spread to other organs throughout the body—a process known as metastasis—which makes treatment incredibly challenging. In fact, metastatic cancers—and not the original tumor—are responsible for most cancer deaths.

"Studying the moment where and when a relatively passive tumor cell acquires the ability to move and metastasize could be a game changer for cancer treatment," said Carlos Carmona-Fontaine, an associate professor of biology at New York University and the study's senior author. "Unfortunately, it is virtually impossible to directly witness this transition, and as a result, there are no therapies that target this critical but understudied step in the progression of cancer."

Most metastatic cells arise from crevasses deep within tumor tissues where oxygen and nutrients are scarce. This resource scarcity is essential in triggering metastases. However, because this scarcity happens in cells buried within hard-to-reach tumor regions, it is challenging to observe directly—in patients, animal cancer models, and even in other lab-based tumor models.

The researchers decided to tackle this problem by building a tiny tumor model that replicates the specific conditions that promote the acquisition of metastatic properties in tumor cells. The model—which they named "3MIC" for the 3D microenvironment chamber—follows the evolution of malignant cells using live microscopy, which images cells in real time.

Using 3D printing technologies, the researchers designed the model with unique geometry to allow for imaging these deep and nutrient-starved cells with unprecedented detail.

Lung cancer cells grown inside the 3MIC over 72 hours. Tumor cells on the left were grown under normal conditions, while tumor cells on the right were grown in a nutrient- and oxygen-scarce region within the 3MIC, producing streams of migratory cells and a dramatic change in the shape of the tumor cluster. Credit: Carmofon Lab/NYU

"One of the most important conditions in the emergence of metastasis—this lack of nutrients and oxygen—was also one of the most difficult to recreate and probably the most important innovation of the 3MIC," said Carmona-Fontaine.

The 3MIC also allowed the researchers to add additional cells, such as macrophages and fibroblasts, that are known to partner with the tumor during the metastatic process. As a result, they were able to study how tumor cells migrate, invade, and interact with these other cells under different metabolic conditions.

In their study, the researchers first confirmed that known metastasis-promoting factors, such as low oxygen, were also relevant in the 3MIC. Interestingly, their data not only confirmed this but also suggested a mechanism where low oxygen indirectly promotes metastasis through lowering the pH of the local tumor environment and making it more acidic.

The researchers also showed that drugs—specifically, versions of the chemotherapy Taxol—that effectively target tumor cells under normal conditions failed to act on the resource-deprived tumor cells, thus sparing them. This may suggest that metastatic cancers' lower drug response may be due to intrinsic changes that make cells more drug-resistant, not lower drug concentration—a distinction that was previously difficult to measure.

"In other words, the conditions we observe in the 3MIC may create an environment that protects tumors from at least some treatments, which may help us begin to explain why metastases are so difficult to treat," said Carmona-Fontaine.

With the 3MIC in hand, the researchers are now focused on finding early signs of cancer metastasis before the cells spread, which could be used as a diagnostic tool to predict metastasis and to test possible therapeutic targets that could interrupt this process.

In addition to Carmona-Fontaine, study authors include Libi Anandi, Jeremy Garcia, Manon Ros, Libuše Janská, and Josephine Liu of NYU's Center for Genomics & Systems Biology.

More information: Libi Anandi et al, Direct visualization of emergent metastatic features within an ex vivo model of the tumor microenvironment, Life Science Alliance (2024). DOI: 10.26508/lsa.202403053

Provided by New York University