Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

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 2,500+ scientific posters on ePosters
  • More than 3,800+ 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

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
Researchers Tune in to Protein Pairs
Rice University team quantifies how mutations affect cell signaling in bacteria.
Tuesday, January 28, 2014
New Statistical Tools Being Developed for Mining Cancer Data
Team from Rice, BCM, UT Austin tackling big data variety.
Monday, December 02, 2013
Rice Writes Rules for Gene-Therapy Vectors
Researchers compute, then combine benign viruses to fight disease.
Thursday, August 15, 2013
Multitasking Plasmonic Nanobubbles Kill some Cells, Modify Others
Rice University discovery could simplify and improve difficult processes used to treat diseases, including cancer.
Thursday, December 06, 2012
Genome of Saltwater Creature could Aid Understanding of Gene Grouping
The genetic code of a simple saltwater creature could help researchers learn more about how groups of genes function in humans and other species.
Friday, August 22, 2008
Changing Environment Organizes Genetic Structure
Study finds biological complexity arises from self-organizing structure of genes.
Monday, November 19, 2007
Scientific News
Poor Survival Rates in Leukemia Linked to Persistent Genetic Mutations
For patients with an often-deadly form of leukemia, new research suggests that lingering cancer-related mutations – detected after initial treatment with chemotherapy – are associated with an increased risk of relapse and poor survival.
Searching Big Data Faster
Theoretical analysis could expand applications of accelerated searching in biology, other fields.
Growing Hepatitis C in the Lab
Recent discovery allows study of naturally occurring forms of hepatitis C virus (HCV) in the lab.
Inciting an Immune Attack on Cancer Cells
A new minimally invasive vaccine that combines cancer cells and immune-enhancing factors could be used clinically to launch a destructive attack on tumors.
Reprogramming Cancer Cells
Researchers on Mayo Clinic’s Florida campus have discovered a way to potentially reprogram cancer cells back to normalcy.
Genetic Overlapping in Multiple Autoimmune Diseases May Suggest Common Therapies
CHOP genomics expert leads analysis of genetic architecture, with eye on repurposing existing drugs.
Surprising Mechanism Behind Antibiotic-Resistant Bacteria Uncovered
Now, scientists at TSRI have discovered that the important human pathogen Staphylococcus aureus, develops resistance to this drug by “switching on” a previously uncharacterized set of genes.
How DNA ‘Proofreader’ Proteins Pick and Edit Their Reading Material
Researchers from North Carolina State University and the University of North Carolina at Chapel Hill have discovered how two important proofreader proteins know where to look for errors during DNA replication and how they work together to signal the body’s repair mechanism.
Fat in the Family?
Study could lead to therapeutics that boost metabolism.
Tissue Bank Pays Dividends for Brain Cancer Research
Checking what’s in the bank – the Brisbane Breast Bank, that is – has paid dividends for UQ cancer researchers.
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
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!