Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

A New Door Opens in Colon Cancer

Published: Tuesday, December 18, 2012
Last Updated: Tuesday, December 18, 2012
Bookmark and Share
Risk factors for the disease are varied and include factors such as advanced age and diet, but most cases share something crucial that scientists hope can usher in new treatments.

In nearly all cases, the DNA in colon tumors harbors mutations in a key intracellular process or “pathway,” leading to the buildup of proteins that drive uncontrolled growth of cells.

Because disruptions in this pathway, known as the Wnt/beta-catenin pathway, are so ubiquitous in colon cancer and other cancers, it represents a promising target for developing therapeutics. However, scientists have so far been unsuccessful in targeting the pathway. Broad Institute senior associate member William Hahn, who is also an associate professor at the Dana–Farber Cancer Institute and Harvard Medical School, describes the situation as being stuck in a room with only one exit. Scientists thought that beta-catenin had only one partner protein, a transcription factor called TCF4, through which it worked to initiate and drive cancer. With no way to target TCF4, it was as though the single door to a potential new therapy remained locked.

A new door may now be open, thanks to an ambitious effort from researchers at the Broad Institute and Dana-Farber Cancer Institute. The work, led by Hahn and made possible by the Broad’s large-scale RNA interference and cell line resources, reveals an alternative pathway through which beta-catenin drives cancer, one that may be more amenable to therapeutic targeting. The findings appear online December 13 in the journal Cell and help suggest an expanded role for proteins like beta-catenin — that they may have more than one path in the cell and more than one role in cancer.

The new study was motivated not only by the desire for new therapeutic targets, but also by the need for a deeper understanding of beta-catenin’s workings in the cell. Recent genome sequencing studies, some completed at the Broad, revealed that beta-catenin’s traditional partner protein, TCF4, was actually missing or inactivated in more than a quarter of cases of colon cancer. The absence of this key partner suggested that beta-catenin had other partner proteins — indicating potential hidden pathways through which it worked to cause cancer.

To begin the hunt for a new pathway, the team set out to find genes that were essential to the survival of cancers driven by beta-catenin, representing its potential partners in the cell. They first classified 85 cell lines from the Broad-Novartis Cancer Cell Line Encyclopedia based on whether beta-catenin was activated (as it is in most colon cancers) or not. In parallel, they analyzed data on those cell lines from an RNA interference screen completed as part of the Cancer Program’s Project Achilles, which identified genes essential for the survival of cancer cells, the so-called “Achilles heels” of cancer.

The results pointed to genes that regulate a protein called YAP1, which controls the activity of other genes. Through extensive follow-up work in cellular and animal models, the team discovered a new complex of proteins that work together with beta-catenin to regulate the transcription, or activity, of genes that drive cancer. Further, they found that the new complex is regulated by YES1, an enzyme in the kinase family of proteins that have proven to be more amenable to therapeutic targeting than transcription factors. The team was even able to use a small molecule to inhibit YES1, blocking the activity of the complex and halting the growth of cancer cells.

“It’s a bit of a surprising finding because most of us thought that beta-catenin has one partner — TCF4 — that’s responsible for all its roles in cancer,” said Hahn. The new results help explain how cancer cells without a working TCF4 protein could still be cancerous. “By finding that there’s another set of partners that beta-catenin could have, it helps explain those findings and it may allow us to have an idea about how these complexes play different roles at different stages of tumor development.”

The discovery of beta-catenin’s new pathway was made possible by the Broad’s resources for large-scale, systematic exploration, in addition to informatics expertise. “We’ve been studying this pathway for twenty years, and we didn’t recognize that there was this other, very important component of it,” said Hahn. “It’s because we didn’t have the tools to do it until now.”

“This work demonstrates the power of Project Achilles and the advantage of using so many cell lines,” said Joseph Rosenbluh, first author on the study. “We could identify new things, simply because we have larger numbers than ever before.”

The findings reveal a new branch of the Wnt/beta-catenin pathway that’s likely important in development and cancer. In addition, targeting the pathway through the YES1 kinase may successfully prevent tumor growth in a large percentage of patients, if a safe and effective targeting therapy were developed. The team is currently looking into further studies of an existing drug that is FDA-approved for other conditions and that targets YES1. Finding a way to target the pathway could make a significant impact on the treatment of this disease, because it is altered in such a large proportion of cases. As Rosenbluh explained, “Finding a way to target beta-catenin will allow us to target all colon cancers.”

The work also demonstrates that systematic studies of the function of genes are a very good complement to those aimed at characterizing cancer genomes. “As genome sequencing in cancer and other conditions becomes cheaper and more routine, the emphasis must shift to the understanding of the function of genes,” Hahn said. “This is a good example of how we’re moving in parallel [to sequencing studies] to do that.”

The new pathway increases the complexity of beta-catenin’s role in the cell, but offers significant opportunities, too. “This complexity we’ve uncovered is probably going to get us closer to understanding how things really work,” said Hahn. “A new door has been opened that tells us there are many other ways we can understand this pathway, and that gives us new opportunities to think about intervening. YES1 is a really promising one, but it may be just the first of many things to come.”


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,200+ scientific posters on ePosters
  • More Than 4,800+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

New Device can Study Electric Field Cancer Therapy
Microfluidic device allows study of electric field cancer therapy through low-intensity fields, preventing malignant cells spreading.
Friday, July 08, 2016
Programmable RNA Vaccines
Tests in mice show the vaccines work against Ebola, influenza, and a common parasite.
Wednesday, July 06, 2016
Seeing RNA at the Nanoscale
MIT researchers have developed a new way to image proteins and RNA inside neurons of brain tissue.
Wednesday, July 06, 2016
Tough New Hydrogel Hybrid Doesn’t Dry Out
Water-based material could be used to make artificial skin, longer-lasting contact lenses.
Friday, July 01, 2016
Wireless, Wearable Toxic-Gas Detector
Inexpensive sensors could be worn by soldiers to detect hazardous chemical agents.
Friday, July 01, 2016
New System for Detecting Explosives
Spectroscopic system with chip-scale lasers cuts detection time from minutes to microseconds.
Wednesday, June 01, 2016
Illuminating Hidden Gene Regulators
New super-resolution technique visualizes important role of short-lived enzyme clusters.
Friday, May 27, 2016
Controlling RNA in Living Cells
Modular, programmable proteins can be used to track or manipulate gene expression.
Wednesday, April 27, 2016
Long-Term Drug Release
New tablet attaches to the lining of the GI tract, resists being pulled away.
Thursday, April 07, 2016
Pharmacy on Demand
New, portable system can be configured to produce different drugs.
Monday, April 04, 2016
A Programming Language for Living Cells
New language lets researchers design novel biological circuits.
Monday, April 04, 2016
Why Some Tumors Withstand Treatment
Mechanism uncovered that allows cancer cells to evade targeted therapies.
Thursday, March 17, 2016
Cancer Cells Remodel Environments Before Spreading
Researchers at MIT have found that the cancer cells remodel their environment to make it easier to reach nearby blood vessels.
Wednesday, March 16, 2016
Paving the Way for Metastasis
Cancer cells remodel their environment to make it easier to reach nearby blood vessels.
Tuesday, March 15, 2016
A New Way to Discover DNA Modifications
Researchers systematically find molecules that help regulate and protect DNA.
Wednesday, March 02, 2016
Scientific News
Liquid Biopsies: Miracle Diagnostic or Next New Fad?
Thanks to the development of highly specific gene-amplification and sequencing technologies liquid biopsies access more biomarkers relevant to more cancers than ever before.
Connectome Map More Than Doubles Human Cortex’s Known Regions
Researchers at NIH have developed software that automatically detects the “fingerprint” of each of these areas in an individual’s brain scans.
Discovered Through ‘Big Data’ Analysis
Researchers at the SBP have identified over 100 new genetic regions that affect the immune response to cancer.
Human Stem Cells to Rapidly Generate Bone, Heart Muscle
A new study shows that combining positive and negative signals can quickly and efficiently steer stem cells down complex developmental pathways to become specialized tissues that could be used in the clinic.
New Mechanism of Tuberculosis Infection
Researchers at UTSW Medical Center have identified a new way that tuberculosis bacteria get into the body, revealing a potential therapeutic angle to explore.
New Therapeutic Targets For Small Cell Lung Cancer Identified
Researchers at UTSW Medical Center have identified a protein termed ASCL1 that is essential to the development of small cell lung cancer and that, when deleted in the lungs of mice, prevents the cancer from forming.
Eliminating Doubt in Criminal Investigations
New ASU certificate to help curb error, misunderstanding in the quest for justice.
Determination of 13 Organic Toxicants in Human Blood
Researchers have utilised liquid-liquid extraction coupling HPLC-MS/MS to identify and quantify organic toxicants in human blood.
A Novel Cell Culture Model For Forensic Biology Experiments
Researchers have developed a new cell culture model which provides an efficient research tool in forensic biology.
Rhino DNA Bank Aids Anti-Poaching Fight
At the University of Pretoria's Veterinary Genetics Laboratory (VGL) at Onderstepoort, Dr Cindy Harper and her team have developed a ground-breaking technique to collect and catalogue DNA from rhinos and rhino horns.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,200+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,800+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!