Cancers May Spread, But They Don’t Forget Where Home Is

by Harrison Ngue
figures by Allie Elchert

Think of a house with a termite problem. The infestation may start behind the wooden paneling in the garage, but over time, it begins to spread. Where you find termites later on depends on two factors: if the termites are able to get to the new location, and how well they can survive once they get there. You’re unlikely to find them in the attic, as it is distant and poorly connected, making it hard to reach. The termites might find their way to a bathroom, only to discover it’s built from tile and offers no nourishment. So even if termites manage to reach many parts of the house, they can only persist where the environment supports their survival. Otherwise, they must retreat, or die off.

Cancer cells spread in a similar fashion. A tumor often begins in one part of the body—say, the pancreas. However, in many cases, some cells break away and travel through the bloodstream to new parts of the body, like the liver or lungs. This process, called metastasis, is responsible for over 90% of cancer-related deaths.

Metastasis unfolds in several steps (Figure 1). First comes local invasion, where cancer cells push into the surrounding tissue. Then, a few cells break away from the main tumor and slip into the nearby blood vessels (intravasation), where they can be carried to any part of the body. Eventually, a few rare cancer cells exit the bloodstream and attempt to settle in a new organ, growing and forming a new tumor (colonization).

Colonization is often the most challenging step for cancer cells because they cannot grow in organs that do not have the right conditions. For example, organs may not have the right nutrients or the immune system may be too hostile. Scientists often describe this using a theory known as the “seed and soil” hypothesis, which dates back to the 1800s. In this theory, the cancer cell is the seed, and the organ it lands in is the soil. Much like a seed, a cancer cell can only grow if it lands in soil with the right nutrients and conditions.

There’s no place like home

Researchers have spent decades studying how cancer cells adapt and evolve to survive in new environments. Yet,  one question remains largely unexplored: Once a cancer cell has settled in a new organ, does it change? Or does it still behave like it belongs in its original home? In other words, if a pancreatic cancer cell ends up in the liver, does it start acting like a liver cancer cell, or does it keep acting like a pancreatic one?

This is the question a team at MIT’s Koch Institute for Integrative Cancer Research set out to answer. The researchers used a well-established mouse model of pancreatic ductal adenocarcinoma, one of the deadliest cancers. They isolated cancer cells from three different places: primary tumors in the pancreas (to understand cancer cells in their natural environment) and cancer cells originally from the pancreas that had metastasized into either the liver or the lungs (to understand how cancer cells can adapt to a new environment).

The team then re-implanted these cells into healthy mice, placing them either in the pancreas, the liver, or a neutral “flank” site (just below the skin, with no special ties to any organ). The logic was simple: If metastatic cells originally from the pancreas had adapted to their new sites, then liver-derived cells should grow better in the liver and lung-derived cells should grow better in the lung. If their origin still dictated their behavior, then they should grow best in the pancreas, no matter where they had metastasized to.

The researchers found the latter: pancreatic cancer cells, whether they came from a primary tumor or a liver or lung metastasis, grew significantly better in the pancreas than in the liver or flank site (Figure 2). Tumors in the pancreas were up to four times larger, showed faster cell growth, and had lower rates of cell death than the same cells placed in the liver or flank. Surprisingly, even after surviving in a new environment, the cancer cells behaved as if they had never left home.

So why do the cancer cells still keep parts of their original identity?

Why would a cancer cell that has already lived in a new organ still grow best in its old one? What was holding it back from fully adapting? The researchers suspected the answer had something to do with the way cancer cells consume and process nutrients—in other words, their metabolism.

Why look at metabolism? Because each organ in the body has a different mix of nutrients available, cancer cells that start in different organs learn to rely on different fuel sources. For example, cancer cells that grow in the pancreas typically depend on glucose and glutamine, while cancer cells that grow in the liver often use more fats and other amino acids. So if a pancreatic cancer cell moved to the liver and truly adapted to its new environment, you would expect it to start using up more fats and other amino acids, just like liver cancer cells.

But that’s not what happened. Even after pancreatic cancer cells had spread to the liver, they continued to use glucose and glutamine the same way they did in the pancreas. They did not switch to the types of nutrients that liver cancer cells prefer. This showed that their metabolism was still shaped by the organ they came from, not the one they had moved to (Figure 3).

That might sound like a small detail, but it has big implications. If metastatic cancer cells continue to rely on the same fuel they used in their original organ, that makes them more predictable—and potentially more vulnerable. It means that treatments designed for the original tumor might still work, even after the cancer has spread. Instead of needing a whole new plan for every new site, we might be able to target the same vulnerability again and again. If we know what cancer cells are still hungry for, we can find smarter ways to cut off their food supply.

To make sure this wasn’t just a short-term effect, the scientists pushed the experiment further. First, they let pancreatic cancer cells grow in the liver or lung of a mouse. Then, they took those same cancer cells and transplanted them into the liver or lung of a second mouse. They repeated this process for up to eight rounds, each time using cells from the previous mouse. This allowed the cancer cells to live in a new organ environment for months, giving them many chances to adapt and change their metabolism. But even after all those generations of growing in a new organ, when the cells were finally placed back in the pancreas, they still grew better there than anywhere else. Their basic metabolism hadn’t changed.

Finally, to confirm that this wasn’t unique to pancreatic cancer, the researchers ran similar experiments using lung cancer and liver cancer. The same trend held–lung cancer cells grew best in the lung and liver cancer cells grew best in the liver. Each cancer type appeared metabolically tied to its tissue of origin.

What does this mean for cancer treatment?

For decades, much of cancer research has focused on the remarkable ability of cancer cells to adapt, evolve, and survive in unfamiliar territory. But this study challenges that assumption. Many cancer cells, it turns out, don’t fully adapt. They bring their original needs and behaviors with them. They arrive at new organs with a somewhat inflexible metabolism, and when the ideal mix of nutrients they grew up consuming isn’t available, their growth is limited. 

That’s not just an interesting biological quirk, it’s a potential weakness. If metastases retain the same metabolic dependencies as the primary tumor, then treatments targeting those metabolic traits could work across the entire body. For example, pancreatic tumors are known to rely heavily on glutamine metabolism, and several drugs are currently being tested to block this pathway, such as CB-839 (also known as telaglenastat), a glutaminase inhibitor. If metastatic pancreatic cancer cells still depend on glutamine even after spreading, then a drug like this could remain effective no matter where in the body the pancreatic cancer has moved to.

Looking ahead, this research suggests a new way of thinking. Rather than just tracking where cancer spreads, we may begin asking how it behaves and whether it’s still playing by the rules of its origin. If we can map which cancers are metabolically inflexible, we might one day learn how to cut off their fuel supply or design treatments that push them into environments where they simply can’t grow. After all, even termites that make it to the bathroom or basement still crave the wood they chewed in the garage. Cancer cells, it turns out, aren’t so different.

Harrison Ngue is an MD-PhD student at Harvard Medical School and the Massachusetts Institute of Technology. He graduated from Harvard College with a degree in biomedical engineering and history of science. His research focuses on cancer biology. He is the founder of the animated educational YouTube channel “Powerhouse of the Cell.” Twitter/X: @harrison_ngue

Allie Elchert is a Ph.D. candidate in the Biological and Biomedical Sciences program at Harvard Medical School, where she is studying transcription regulatory processes in yeast.

Cover image by skylarvision on Pixabay.

For More Information:

• The American Cancer Society has a brief primer about how cancers spread. 
• This YouTube video by Ted-Ed illustrates the process by which cancer cells metastasize.
• This article from WedMD describes how different types of cancers depend on different nutrients, and how this has allowed researchers to design new targeted therapies.
• In this TED talk, Dr. Sophia Lunt, an associate professor of Biochemistry & Molecular Biology at Michigan State University and former postdoctoral fellow at MIT, discusses how cancer cells rely on metabolic pathways that normal cells can live without, revealing opportunities to ‘starve’ cancer.