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

Physicists Decode Decision Circuit of Cancer Metastasis

Published: Thursday, October 31, 2013
Last Updated: Thursday, October 31, 2013
Bookmark and Share
Rice U. research reveals three-way genetic switch for cancer metastasis.

Cancer researchers from Rice University have deciphered the operating principles of a genetic switch that cancer cells use to decide when to metastasize and invade other parts of the body. The study found that the on-off switch’s dynamics also allows a third choice that lies somewhere between “on” and “off.” The extra setting both explains previously confusing experimental results and opens the door to new avenues of cancer treatment.

“Cancer cells behave in complex ways, and this work shows how such complexity can arise from the operation of a relatively simple decision-making circuit,” said study co-author Eshel Ben-Jacob, a senior investigator at Rice’s Center for Theoretical Biological Physics (CTBP) and adjunct professor of biochemistry and cell biology at Rice. “By stripping away the complexity and starting with first principles, we get a glimpse of the ‘logic of cancer’ — the driver of the disease’s decision to spread.”

In the PNAS study, Ben-Jacob and CTBP colleagues José Onuchic, Herbert Levine, Mingyang Lu and Mohit Kumar Jolly describe a new theoretical framework that allowed them to model the behavior of microRNAs in decision-making circuits. To test the framework, they modeled the behavior of a decision-making genetic circuit that cells use to regulate the forward and backward transitions between two different cell states, the epithelial and mesenchymal. Known respectively as the E-M transition (EMT) and the M-E transition (MET), these changes in cell state are vital for embryonic development, tissue engineering and wound healing. During the EMT, some cells also form a third state, a hybrid that is endowed with a special mix of both epithelial and mesenchymal abilities, including group migration.

The EMT transition is also a hallmark of cancer metastasis. Cancer cells co-opt the process to allow tumor cells to break away, migrate to other parts of the body and establish a new tumor. To find ways to shut down metastasis, cancer researchers have conducted dozens of studies about the genetic circuitry that activates the EMT.

One clear finding from previous studies is that a two-component genetic switch is the key to both the EMT and MET. The switch contains two specialized pairs of proteins. One pair is SNAIL and microRNA34 (SNAIL/miR34), and the other is ZEB and microRNA200 (ZEB/miR200).

Each pair is “mutually inhibitory,” meaning that the presence of one of the partners inhibits the production of the other.

In the mesenchymal cell state — the state that corresponds to cancer metastasis — both SNAIL and ZEB must be present in high levels. In the epithelial state, the microRNA partners dominate, and neither ZEB nor SNAIL is available in high levels.

“Usually, if you have two genes that are mutually limiting, you have only two possibilities,”
Ben-Jacob said. “In the first case, gene A is highly expressed and inhibits gene B. In the other, gene B is highly expressed and it inhibits A. This is true in the case of ZEB and miR200. One of these is ‘on’ and the other is ‘off,’ so it’s clear that this is the decision element in the switch.”

SNAIL and miR34 interact more weakly. As a result, both can be present at the same time, with the amount of each varying based upon inputs from a number of other proteins, including several other cancer genes.

“One of the most important things the model showed us was how SNAIL and miR34 act as an integrator,” Ben-Jacob said. “This part of the circuit is acted on by multiple cues, and it integrates those signals and feeds information into the decision element. It does this based upon the level of SNAIL, which activates ZEB and inhibits miR200.”

In modeling the ZEB/miR200 decision circuit, the team found that it operates as a “ternary” or three-way, switch. The reason for this is that ZEB has the ability to activate itself by a positive feedback loop, which allows the cell to keep intermediate levels of all four proteins in the switch under some conditions.

Ben-Jacob said the hybrid, or partially on-off state, also supports cancer metastasis by enabling collective cell migration and by imparting stem-cell properties that help migrating cancer cells evade the immune system and anticancer therapies.

“Now that we understand what drives the cell to select between the various states, we can begin to think of new ways to outsmart cancer,” Ben-Jacob said. “We can think about coaxing the cancer to make the decision that we want, to convert itself into a state that we are ready to attack with a particularly effective treatment.”

The cancer-metastasis results correspond with findings from previous studies by Ben-Jacob and Onuchic into the collective decision-making processes of bacteria and into new strategies to combat cancer by timing the delivery of multiple drugs to interrupt the decision-making processes of cancer.

“At CTBP, we allow the underlying physics of a system to guide our examination of its biological properties,” said Onuchic, CTBP co-director and Rice’s Harry C. and Olga K. Wiess Professor of Physics and Astronomy and professor of chemistry and of biochemistry and cell biology. “In this case, that approach led us to develop a powerful model for simulating the decision-making circuitry involved in cancer metastasis. Going forward, we plan to see how this circuit interacts with others to produce a variety of cancer cells, including cancer stem cells.”

The research is supported by the National Science Foundation, the Cancer Prevention and Research Institute of Texas and the Tauber Family Funds at Tel Aviv University. Lu is a postdoctoral researcher at CTBP, and Jolly is a graduate student in bioengineering. Levine is co-director of CTBP and Rice’s Karl F. Hasselmann Professor in Bioengineering. Ben-Jacob is also the Maguy-Glass Professor in Physics of Complex Systems and professor of physics and astronomy at Tel Aviv University.

Further Information
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 2,800+ scientific posters on ePosters
  • More Than 4,000+ 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 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

Chemical Design Made Easier
Rice University scientists prepare elusive organocatalysts for drug and fine chemical synthesis.
Wednesday, November 25, 2015
Biomarker Finder Adjusts On the Fly
Rice University scientists build better tool to find signs of disease.
Thursday, October 22, 2015
Gene On-Off Switch Works Like Backpack Strap
Texas Medical Center-based team unravels how loops form in genome.
Thursday, October 22, 2015
Structure of Protein at Root of Muscular Disease Decoded
Researchers at Rice University and Baylor College of Medicine have unlocked the structural details of a protein seen as key to treating a neuromuscular disease.
Thursday, October 01, 2015
Researchers Find New Clue to Halting Leukemia Relapse
A protein domain once considered of little importance may be key to helping patients who are fighting acute myeloid leukemia (AML) avoid a relapse.
Friday, September 11, 2015
Imaging Software Could Speed Breast Cancer Diagnosis
Technology could improve access to diagnostic services in developing countries.
Wednesday, August 26, 2015
Researchers Strategize to Outsmart Bacteria
Rice University lab identifies mutations that allow bacteria to resist antibiotics.
Thursday, August 06, 2015
Cancer Treatment Models get Real
Researchers at Rice Univ. and Univ. of Texas MD Anderson Cancer Center have developed a way to mimic the conditions under which cancer tumors grow in bones.
Thursday, August 06, 2015
Bacteria Use DNA Replication to Time Key Decision
Rice University researchers have found that in spore-forming bacteria, chromosomal locations of genes can couple the DNA replication cycle to critical decisions about whether to reproduce or form spores.
Monday, July 13, 2015
Massive Genome Shift in one Generation
A team of biologists has discovered that an agricultural pest that began plaguing U.S. apple growers in the 1850s likely did so after undergoing extensive and genome-wide changes in a single generation.
Tuesday, June 16, 2015
DNA Mutations get Harder to Hide
Rice University researchers have developed a method to detect rare DNA mutations with an approach hundreds of times more powerful than current methods.
Wednesday, May 27, 2015
Amniotic Stem Cells Demonstrate Healing Potential
Rice University, Texas Children’s Hospital study proves cells promote vasculature in hydrogel therapy.
Friday, April 10, 2015
Cells Exercise Suboptimal Strategy to Survive
Rice University study shows it’s not always good for cells’ metabolism to work at peak efficiency.
Thursday, April 09, 2015
Designing A Better Way To Study Stomach Flu
Texas Medical Center team aims to improve research of gastrointestinal disease.
Wednesday, March 18, 2015
Worm Virus Details Come to Light
Rice University scientists have won a race to find the crystal structure of rare nematode virus, known to infect the most abundant animal on Earth.
Wednesday, August 20, 2014
Scientific News
High Throughput Mass Spectrometry-Based Screening Assay Trends
Dr John Comley provides an insight into HT MS-based screening with a focus on future user requirements and preferences.
Revolutionary Technologies Developed to Improve Outcomes for Lung Cancer Patients
Breath test to detect lung cancer brings oxygen directly to the wound.
NIH Supports New Studies to Find Alzheimer’s Biomarkers in Down Syndrome
Initiative will track dementia onset, progress in Down syndrome volunteers.
Dementia Linked to Deficient DNA Repair
Mutant forms of breast cancer factor 1 (BRCA1) are associated with breast and ovarian cancers but according to new findings, in the brain the normal BRCA1 gene product may also be linked to Alzheimer’s disease.
Using Drug-Susceptible Parasites to Fight Drug Resistance
Researchers at the University of Georgia have developed a model for evaluating a potential new strategy in the fight against drug-resistant diseases.
Boosting Breast Cancer Treatment
To more efficiently treat breast cancer, scientists have been researching molecules that selectively bind to cancer cells and deliver a substance that can kill the tumor cells, for several years.
New Gene Map Reveals Cancer’s Achilles’ Heel
Team of researchers switches off almost 18,000 genes
New Discovery Sheds Light on Disease Risk
Gaps between genes interact to influence the risk of acquiring disease.
How Cells ‘Climb’ to Build Fruit Fly Tracheas
Mipp1 protein helps cells sprout “fingers” for gripping.
Research Finding Could Lead to Targeted Therapies for IBD
Findings published online in Cell Reports.
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
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos