Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study pinpoints novel cancer gene and biomarker

25.06.2009
Research underscores need to combine genomics and basic biology in cancer gene hunt

Dana-Farber Cancer Institute scientists' discovery of a cancer-causing gene – the first in its family to be linked to cancer – demonstrates how the panoramic view of genomics and the close-up perspective of molecular biology are needed to determine which genes are involved in cancer and which are mere bystanders. The findings are reported in the June 25 issue of the journal Nature.

"In the coming years, we can expect genomic studies [which chart the activity of thousands of cell genes] to generate hundreds or thousands of genetic elements of interest in cancer research," says the study's senior author, Lynda Chin, MD, of Dana-Farber. "To narrow that group to the genes that actually drive cancer growth and metastasis, it's necessary to do functional studies, which focus on what individual genes do to turn a cell cancerous, and mechanistic studies, which examine how they turn cells cancerous and in what setting. It is a long and intensive effort that will leverage knowledge from different fields and different model systems."

In the study, Chin, lead author Kenneth Scott, PhD, of Dana-Farber, and their colleagues worked their way through a series of experiments -- in yeast cells, multiple types of human cancer cells, laboratory cell cultures, and mouse models - to demonstrate that a surplus of a gene known as GOLPH3 can spur cancer cell growth in a variety of tissues. It is the first gene associated with the Golgi complex, a tiny packaging plant that prepares proteins for their journey within and outside the cell, which has been found to play a role in cancer. Chin's team also found that the protein made from GOLPH3 may serve as a biomarker for tumors that can be effectively treated with the chemotherapy drug rapamycin: tumors with a high level of the protein are more apt to shrink in response to the drug than those with low levels.

The study began with an observation made years ago that a section of chromosome 5p13 is often duplicated, or amplified, in cancers of the lung, ovary, breast, and prostate gland, as well as melanoma. The presence of this abnormality in so many different types of cancer led Chin and her associates to take a closer look at that stretch of chromosome to see what genes reside there.

Using a method called genomic qPCR that can pick out specific sequences of DNA, they found four genes in the amplified region, two of which, GOLPH3 and SUB1, were expressed at high levels, due to the increase in gene copy. To determine whether both, or either, of these genes are involved in cancer, they conducted "loss of function" tests, in which they lowered each gene's activity in a set of lab-grown tumor cells. "When we 'knocked down' GOLPH3 expression [or activity] by 95 percent, it significantly inhibited the ability of these cell lines to grow in a semi-solid condition, a cancerous quality that normal cells do not typically share," Chin says. "Knocking down SUB1 to a comparable level had only a minimal effect."

Intriguing as this finding was, it was hardly enough to prove that GOLPH3 is an oncogene -- a contributor to cancer when overexpressed within a cell. Demonstrating that would require several experiments to ensure that GOLPH3 itself, and not a nearby "shadow" gene, is responsible for the effects. Next came gain-of-function studies to see whether revving up GOLPH3 activity can turn a non-cancerous cell cancerous. It did in both mouse and human cells.

"All these results enabled us to build a case that GOLPH3 is an oncogene," Chin states. But there was a problem. "This information wasn't very helpful for achieving our ultimate goal, which is the translation of our findings into a form that is clinically useful for patients."

Despite their discovery that GOLPH3 can promote cancer, researchers didn't know what the gene's role is in normal cells. "There was literally no information on what it does," Chin remarks. The only hint was that the protein it encodes -- designated GOLPH3 -- is found in the Golgi network.

The team's first attempt to uncover GOLPH3's role -- using gene expression profiling to see how protein levels track with various cell functions -- was fruitless. So the researchers ran experiments with yeast cells to see which proteins share GOLPH3's cell neighborhood and which proteins it interacts with.One such partner was found to be VPS35, a component of a structure called the retromer complex. The complex's job is to recycle the antenna-like receptors that dot the cell surface.

From the many genetic screening tests that have been done in yeast, researchers knew that flaws in the retromer complex can cause cells to be vulnerable to rapamycin, just as excess GOLPH3 can. Rapamycin is known to interfere with a protein called TOR, whose job is to control yeast cell size. This suggested that the retromer complex in yeast is important for chemical signals sent to and from TOR.

Chin's team theorized that mammalian GOLPH3 also works with the retromer complex to control the activity of TOR in mammal cells (where it's known at mTOR). To test this idea, the investigators found that knocking down GOLPH3 reduced cell size just as rapamycin did. They followed those experiments with biochemical studies to explore how GOLPH3 affects cell size.

The team next sought to answer whether high GOLPH3 levels cause tumor cells to be more susceptible to rapamycin in animal studies. They took two sets of human melanoma skin cancer cells -- one of which had excess GOLPH3 and the other had normal levels -- implanted them in animals, allowed them to grow into tumors, then treated them with rapamycin. "In the animals where GOLPH3 was overexpressed, the cancer cells grew much faster, but the tumors were much more responsive to rapamycin," Chin notes, "suggesting the tumor-promoting effect of GOLPH3 is dependent on mTOR signaling."

Lastly, the team considered whether the same mechanism might be at work in human cancer cells. An experiment analyzing human tumor tissue for specific proteins suggested yes. The researchers found that non-small cell lung cancer cells with too many copies of the GOLPH3 gene also had abnormally high levels of mTOR activity. "The mechanistic relationship we'd identified in the mouse system is also at work in human tumors," says Chin, who is also an associate professor at Harvard Medical School.

In addition to identifying GOLPH3 as a bona fide oncogene and an indicator of whether rapamycin is likely to be effective against specific tumors, the study points to the need to follow genomic studies with a rigorous examination of the biological purpose and operation of potential cancer genes, Chin concludes. "Only then can we turn our intriguing discoveries in the cancer genome into something that is useful to cancer patients."

The study was supported by a grant from the National Institutes of Health.

Co-authors include Omar Kabbarah, Mei-Chih Liang, PhD, Joyce Wu, Sabin Dhakal, Min Wu, PhD, Shujuan Chen, Tamar Feinberg, Joseph Huang, Hans Widlund, PhD, and Kowk-Kin Wong, MD, PhD, Dana-Farber; Elena Ivanova, PhD, Yonghong Xiao, PhD, and Alexei Protopopov, PhD, Dana-Farber and the Broad Institute of Advanced Cancer Science; David E. Fisher, MD, PhD, Massachusetts General Hospital; Valsamo Anagnostou, and David Rimm, MD, PhD,Yale University School of Medicine; Abdel Saci, PhD, Harvard Medical School.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

Bill Schaller | EurekAlert!
Further information:
http://www.dfci.harvard.edu

More articles from Life Sciences:

nachricht Closing the carbon loop
08.12.2016 | University of Pittsburgh

nachricht Newly discovered bacteria-binding protein in the intestine
08.12.2016 | University of Gothenburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Closing the carbon loop

08.12.2016 | Life Sciences

Applicability of dynamic facilitation theory to binary hard disk systems

08.12.2016 | Physics and Astronomy

Scientists track chemical and structural evolution of catalytic nanoparticles in 3-D

08.12.2016 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>