A New Stem Cell Approach to Cancer Prevention, Straight From the Gut

The Problem: Colon cancer is responsible for the second highest number of cancer deaths in the United States, and third highest worldwide. The majority of cases are thought to be caused by mutations in a gene called APC that cause intestinal stem cells to overpower neighboring unmutated ones, leading to uncontrolled growth and tumor formation. It has remained unclear how exactly these mutated stem cells outcompete their healthy counterparts. 

The Study: APC-mutant cells release harmful molecules that interfere with healthy stem cells and allow mutated ones to overwhelm them, shows a new Nature study led by NYSCF – Robertson Stem Cell Investigator Louis Vermeulen, MD, PhD, of Amsterdam University Medical Center. The team also found that lithium, commonly prescribed for psychiatric conditions, can prevent tumor formation caused by APC-mutant stem cells in mice.

Why It Matters: The results of the study, which pinpoint the mechanism likely driving most colon cancer cases, have led to a new clinical trial to test whether lithium drugs can prevent colon cancer in genetically predisposed patients. 

Inside our gut is a complex balance of processes that ensure regular renewal of the intestinal lining. Despite its delicate regulation, this system can be hijacked and inactivated by intestinal stem cells with mutations in the tumor suppressor gene APC. In these cases, mutants overtake the surrounding healthy gut stem cells and often cause the affected person to develop Familial Adenomatous Polyposis (FAP). Individuals with FAP are almost certain to develop colon cancer, one of the most fatal cancer types. Additionally, APC mutations are found in about 80% of all human colon cancers, making it a salient target for developing new treatments.

Until this study, scientists didn’t know how exactly this mutation prompted a takeover of healthy intestinal stem cells. After careful examination in models of normal vs mutated cells, the team found an answer to their question in “super-competition.”

The Secrets of Super-competition 

To better understand how APC-mutated stem cells out-compete their neighbors, the team turned to colon organoids — 3D clusters of colon cells — made from either healthy or cancerous colon tissue. Researchers “mixed and matched” organoids derived from healthy and mutated cells to examine differences in how the cells behaved. The team then observed that stem cells with APC mutations release chemical signals that inhibit growth of their healthy counterparts. 

“Following the occurrence of a mutation in a key gene that regulates stem cells in the intestine, these cells turn into cheaters that actively suppress the normal cells in the environment,” said Dr. Vermeulen in a press release.

This was a totally unexpected result, as it was previously assumed that the mutant cells were passive players in the intestinal environment and could simply grow faster or live longer than healthy cells. 

“Our findings indicate that cells on their way to a full malignancy can actively suppress the stem cells in the vicinity to gain a competitive edge,” Dr. Vermeulen added. “This is a concept we refer to as super-competition.”

Essentially, the researchers’ conclusions paint a far more aggressive picture of APC mutants — one in which they directly target and sabotage competing cells to ensure their own dominance.

From Brain to Gut: A New Use for Lithium

Next, the team turned their attention to strategies for rescuing healthy stem cells from malignant ones. One potential target was the WNT signaling pathway, a critical cellular process whose dysfunction is frequently implicated in cancer. The team found that APC-mutated stem cells secrete chemicals that disrupt WNT signaling (a major factor in their ability to “supercompete”), prompting them to wonder if restoring the pathway could keep normal cells safe from their mutant neighbors. 

The team decided to test lithium, a drug typically prescribed for psychiatric conditions and known to have some effects on digestive cancers and WNT signals, in mice carrying APC mutations. In an exciting breakthrough, they found that restoring the WNT pathway could protect healthy cells from rogue super-competers, and thus prevent tumors from forming. 

Now, the journey continues in a new clinical trial backed by the Dutch Cancer Society (KWF), which will recruit FAP patients to test the anti-cancer effects of lithium.

“Our clinical trial may reveal that lithium can be used to prevent cancer development in FAP individuals,” noted PhD student Sanne van Neeren, lead author of the study. 

Aside from the clinical trial, which will take place in the Netherlands, another important facet of this work is its potential as a generalizable anti-cancer strategy. Just as malignant cells manipulate their interactions with healthy cells, researchers can fight cancer by manipulating these interactions to let the healthy cells win.

“This is a novel strategy for cancer prevention and could be applied to many heritable cancer syndromes involving different mutations and organs,” says van Neeran, emphasizing the need for further research in this area. 

But this is just the beginning. The Vermeulen team’s work could open entirely new avenues in fighting cancer, ones that incorporate the central role of stem cells in cancer initiation and prevention.

Journal article:

Apc-mutant cells act as supercompetitors in intestinal tumour initiation
Sanne M. van Neerven, Nina E. de Groot, Lisanne E. Nijman, Brendon P. Scicluna, Milou S. van Driel, Maria C. Lecca, Daniël O. Warmerdam, Vaishali Kakkar, Leandro F. Moreno, Felipe A. Vieira Braga, Delano R. Sanches, Prashanthi Ramesh, Sanne ten Hoorn, Arthur S. Aelvoet, Marouska F. van Boxel, Lianne Koens, Przemek M. Krawczyk, Jan Koster, Evelien Dekker, Jan Paul Medema, Douglas J. Winton, Maarten F. Bijlsma, Edward Morrissey, Nicolas Léveillé & Louis Vermeulen. Nature. 2021. DOI: https://www.nature.com/articles/s41586-021-03558-4

Cover image credit: Dirk Gillissen