Manipulating a Single Gene Turns Colorectal Cancer Cells Back to Normal

By Eva Kiesler,

Wednesday, July 1, 2015

Organoid cell structures fluorescing in blue, green, and purple.

Working in mice, Memorial Sloan Kettering scientists have found that genetic alterations in the APC gene, which are found in more than 90 percent of colorectal cancers, play an important role in driving the disease. The researchers are now asking whether potential drugs designed to undo the effects of these mutations could offer a future strategy to control colorectal cancer.

  • More-effective colorectal cancer therapies are urgently needed.
  • The disease was faithfully mimicked in mice using a new method.
  • Restoring APC levels in the mice led to robust anticancer effects.
  • Formerly cancerous cells resumed normal growth and development.
  • The mice stayed cancer free for months.

Memorial Sloan Kettering researchers are unceasingly searching for better ways to treat colorectal cancer, a disease that causes close to 700,000 deaths worldwide each year. One area of particular interest has been a gene called APC, which is mutated in up to nine out of ten colorectal tumors.

Scientists have known for some time that APC mutations, which shut down the gene’s normal activity, can cause the formation of colorectal cancers. But thus far they haven’t been able to tell whether the same gene changes continue to play a role in more-advanced tumors.

Now, for the first time, an MSK study published in the journal Cell shows that APC mutations spur the progression of the disease, suggesting the gene might be a promising target for future drugs. Working in mice, our researchers found that by artificially restoring the gene’s activity — essentially undoing the effect of an APC mutation — it’s possible to revert colorectal cancer cells back to normal and prevent the cancer from returning.

“The results of this study are just really clear cut,” says Cancer Biology and Genetics Program Chair Scott Lowe, who led the research. “It tells us a lot about colorectal cancer from a biologic perspective, and it has important ramifications for potential therapies.”

A Mouse Model Based on RNA Interference

In the study, the researchers developed a new mouse model of colorectal cancer. They engineered the mice using a technology called RNA interference (RNAi), which allowed them to switch off the APC gene and induce colorectal tumors that replicate key features of the disease seen in patients.

In mouse models scientists have used previously to study the disease, the gene was permanently removed, or “knocked out,” Dr. Lowe explains. “Deleting the gene could tell us that APC mutations can lead to cancer, but it couldn’t tell us what restoring APC would do. Once the gene’s gone, you can’t put it back.”

In contrast, when genes are shut down using RNAi technology, their activity can be turned back on. When the researchers restored the expression of APC in the mice, they were surprised by the dramatic effect. Within four days, tumors stopped growing and the mice regained normal intestinal function. After several weeks, all tumors had regressed, and months later the animals’ cancer hadn’t returned.

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Making Colorectal Cancer Cells Normal

“What was even more surprising to us was that restoring APC appeared to transform tumor cells and make them seemingly normal again,” Dr. Lowe notes. “It wasn’t that the cells died or stopped dividing. They seemed to return to their original, noncancerous state and were able to function normally.”

Restoring APC appeared to transform tumor cells and make them seemingly normal.
Scott Lowe
Scott Lowe Chair, Cancer Biology and Genetics Program

For example, the researchers performed experiments using intestinal organoids — small, three-dimensional structures of cells derived from the intestinal glands of mice. The cells within the organoids, which grow together in a way that resembles their natural tissue arrangement, can be used as a tool to study how gene changes may affect colorectal cancer biology.

“When we used RNAi to silence APC, the organoids lost their normal shape and formed spheres, which is typical of how cancer organoids grow,” explains Kevin O’Rourke, a graduate student in our Tri-Institutional MD-PhD program who served as the study’s first author along with research fellow Lukas Dow. “And when we reactivated APC expression, this restored normal cell division and growth.”

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Hints for Future Therapy

The APC gene controls a biological process called the WNT pathway, which is deactivated in most colorectal tumors. The findings suggest it might be possible to develop a new type of drug that reactivates the pathway in colorectal cancer cells.

Such a potential therapy might work against a broad range of APC-mutated tumors, including some that contain additional mutations. In the study, the researchers found that restoring APC expression could also effectively treat mice whose colorectal tumors carried mutations in the genes Kras and p53 — which are found in about half of patients with colorectal cancer.

Dr. Lowe emphasizes that developing a new drug and determining its long-term clinical value could take years. “Earlier studies have shown that completely blocking the WNT pathway could be severely toxic to normal intestinal cells and lead to side effects,” he says. “But our findings suggest that small molecules that have been carefully designed to modulate the pathway — as opposed to blocking it — might achieve effects in patients similar to those we’ve seen when reactivating APC expression in our mouse model.”

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This research was funded by the National Institutes of Health under grant number CA-013106.


This is why , I make everyone that I know, that they have to donate to the hospital only! No other charities love u guy's! U saved me

What is the mechanism used in this therapy? You just mentioned "small molecules ". Please be specific. Thank you.

Thank you for your comment. The small molecules mentioned in the story would be in the form of drugs that have not yet been developed, but there are some details provided in the study suggesting the mechanism of action:

"Our findings have important implications for the clinical utility
of strategies targeting the Wnt pathway, particularly those aimed
at re-engaging the endogenous tumor suppression mechanisms.
First, although it is currently impractical to directly restore
wild-type APC function to CRCs, our results imply that small
molecules that aimed at modulating, but not blocking, the Wnt
pathway, might achieve similar effects. In this regard, the recent
development of small molecule Tankyrase (Tnk) inhibitors, which
modulate Wnt activity by regulating the activity of the b-catenin
destruction complex, represent a positive step in this direction
(Huang et al., 2009; Waaler et al., 2011). Second, we note that
the induction of differentiation upon Apc restoration is extremely
rapid, and occurs well before full Apc expression is restored. This
observation implies that only partial inhibition of hyperactive Wnt
signaling will be required for potent anti-tumor effects, while
sparing surrounding normal tissue."

You can see the entire study (the publication in Cell) here:

Is it possible that this may be of any benefit for use in perineural invasion?

Sara, thank you for your comment. This research is still at an early stage, so we are unable to determine what types of cancer (or form of cancer spread) that this approach will be effective in treating. If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to

How long before clinical trials? My brother has a recurring colon tumor, would he be eligible?

Joseph, thank you for reaching out. As Dr. Lowe mentions in the story, this research is at an early stage, and developing a new drug and determining its long-term clinical value using this approach could take years. If your brother is interested in clinical trials for colorectal cancer at Memorial Sloan Kettering, more can be learned here:

If he would like to make an appointment with a Memorial Sloan Kettering physician for a consultation, he can call our Physician Referral Service at 800-525-2225 or go to Thanks for your comment.

I was just diagnosed with Anal Cancer. Don't know the stage yet. Doing test. Is this drug for manipulating this gene available yet? In trial or otherwise?

Katherine, we're sorry to hear about your diagnosis. Depending on the stage of your cancer and the particular mutations found in your tumor, there may be clinical trials for targeted therapies available to you. If you'd like to learn more by making an appointment at MSK, you can call 800-525-2225 or go to for more information. Thank you for your comment.

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