Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Seemingly invincible cancers stem cells reveal a weakness

06.06.2014

Metastatic cancer cells, which can migrate from primary tumors to seed new malignancies, have thus far been resistant to the current arsenal of anticancer drugs.

Now, however, researchers at Whitehead Institute have identified a critical weakness that actually exploits one of these cells' apparent strengths—their ability to move and invade tissues.

"This is the first vulnerability of invasive cancer cells that we really understand," says Whitehead Member Piyush Gupta, whose lab's latest work is described in the June issue of the journal Cancer Discovery. "For a while we didn't know if they had any vulnerabilities that could be exploited for therapy. Then, a few years ago we discovered they were exquisitely sensitive to some chemical molecules, and therefore had to have a weakness. But we still didn't know at the time what that weakness was. Now we know."

Cancer cells acquire invasive and stem cell-like traits by undergoing a process called an epithelial-to-mesenchymal transition (EMT), which transforms cube-like, immobile cells into elongated, mobile ones. Once mobile, cancer cells can form metastases by using the blood stream as an expressway to distant sites in the body, where they can establish new tumors. In addition to being invasive and metastatic, cancer cells that undergo an EMT are also resistant to radiation and most chemotherapies.

Although they are resistant to most therapies, Gupta and his colleagues had previously identified two compounds with very similar structures that were selectively toxic against the invasive cancer cells that had undergone an EMT, but not their non-invasive counterparts. These unique compounds were discovered in a large screen of over 300,000 chemical compounds.

Intrigued by these compounds that were selectively toxic to metastatic cancer cells, Yuxiong Feng, a postdoctoral researcher in Gupta's lab, further investigated their activity and discovered that the compounds kill by stressing the endoplasmic reticulum (ER) of EMT cells; non-EMT cells were unscathed because their ER was unaffected by these compounds. Feng also found that other chemicals that cause ER stress also similarly dispatched only the metastatic EMT cells. The obvious question was why these otherwise indestructible cells had such sensitive ERs.

A hint lies at the heart of EMT's physiology and function. Invasive cancer cells, like other mesenchymal cells, move by secreting large scaffolding proteins and other proteins that interact with the extracellular matrix, the structural support that holds neighboring cells together. Pumping out these proteins strains the cancer cells' ER to their limit. When Feng treated EMT cells with chemicals that further stressed their ER, the cells died. But when those cells' production of extracellular matrix proteins was artificially blocked, the cells were much less sensitive to the ER-stressing chemicals.

Feng's work points to one specific part of the process, called the PERK pathway, as being particularly important. This pathway helps cells survive the stress of secreting copious amounts of proteins, and in EMT cells, it is always active at a low level. In studying roughly 800 patient tumors (both primary and metastatic) across a range of cancer types, including breast, colon, gastric, and lung, Feng found that the expression of EMT genes was tightly correlated with PERK pathway activity.

"We've found that whenever you have EMT, the PERK pathway is more active," says Feng, who is the first author of the Cancer Discovery paper. "That means we might be able to use PERK pathway activity as a marker to help guide treatment, since tumors with higher PERK activity would likely be more sensitive to further ER stress."

As promising as these developments sound, Feng cautions that further work is needed before PERK screening could become mainstay of cancer diagnostics.

"Our research provides new insights into the biology and weaknesses of invasive cancer cells. Our findings also raise interesting and important questions for further study: how does the PERK pathway support the malignant function of EMT cells? What is the molecular circuitry activated upon EMT that causes cells to secrete copious amounts of extracellular matrix proteins? It's all very exciting."

###

This research is supported by the Richard and Susan Smith Family Foundation and the Breast Cancer Alliance.

Piyush Gupta's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an assistant professor of biology at Massachusetts Institute of Technology.

Full Citation:

"Epithelial-to-mesenchymal transition activates PERK-eIF2a and sensitizes cells to endoplasmic reticulum stress"

Cancer Discovery, June, 2014.

Yuxiong Feng (1), Ethan S. Sokol (1,2), Catherine A. Del Vecchio (1), Sandhya Sanduja (1), Jasper H.L. Claessen (1), Theresa Proia (1), Dexter X. Jin (1,2), Ferenc Reinhardt (1), Hidde L. Ploegh (1,2), Qiu Wang (3), Piyush B. Gupta (1,2, 4, 5, 6).

1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
3. Department of Chemistry, Duke University, Durham, NC 27708, USA
4. Koch Institute for Integrative Cancer Research, Cambridge, MA 02142, USA
5. Harvard Stem Cell Institute, Cambridge, MA 02142, USA
6. Broad Institute, Cambridge, MA 02142, USA

Nicole Giese Rura | Eurek Alert!
Further information:
http://wi.mit.edu/

Further reports about: Biomedical Cancer Department EMT Technology activity function proteins reticulum transition

More articles from Life Sciences:

nachricht Biology in a twist -- deciphering the origins of cell behavior
31.03.2015 | National University of Singapore

nachricht Speech dynamics are coded in the left motor cortex
31.03.2015 | Universitätsmedizin Göttingen - Georg-August-Universität

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Experiment Provides the Best Look Yet at 'Warm Dense Matter' at Cores of Giant Planets

In an experiment at the Department of Energy's SLAC National Accelerator Laboratory, scientists precisely measured the temperature and structure of aluminum as...

Im Focus: Energy-autonomous and wireless monitoring protects marine gearboxes

The IPH presents a solution at HANNOVER MESSE 2015 to make ship traffic more reliable while decreasing the maintenance costs at the same time. In cooperation with project partners, the research institute from Hannover, Germany, has developed a sensor system which continuously monitors the condition of the marine gearbox, thus preventing breakdowns. Special feature: the monitoring system works wirelessly and energy-autonomously. The required electrical power is generated where it is needed – directly at the sensor.

As well as cars need to be certified regularly (in Germany by the TÜV – Technical Inspection Association), ships need to be inspected – if the powertrain stops...

Im Focus: 3-D satellite, GPS earthquake maps isolate impacts in real time

Method produced by UI researcher could improve reaction time to deadly, expensive quakes

When an earthquake hits, the faster first responders can get to an impacted area, the more likely infrastructure--and lives--can be saved.

Im Focus: Atlantic Ocean overturning found to slow down already today

The Atlantic overturning is one of Earth’s most important heat transport systems, pumping warm water northwards and cold water southwards. Also known as the Gulf Stream system, it is responsible for the mild climate in northwestern Europe. 

Scientists now found evidence for a slowdown of the overturning – multiple lines of observation suggest that in recent decades, the current system has been...

Im Focus: Robot inspects concrete garage floors and bridge roadways for damage

Because they are regularly subjected to heavy vehicle traffic, emissions, moisture and salt, above- and underground parking garages, as well as bridges, frequently experience large areas of corrosion. Most inspection systems to date have only been capable of inspecting smaller surface areas.

From April 13 to April 17 at the Hannover Messe (hall 2, exhibit booth C16), engineers from the Fraunhofer Institute for Nondestructive Testing IZFP will be...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

World Conference On Regenerative Medicine 2015: Registration And Abstract Submission Now Open

25.03.2015 | Event News

University presidents from all over the world meet in Hamburg

19.03.2015 | Event News

10. CeBiTec Symposium zum Big Data-Problem

17.03.2015 | Event News

 
Latest News

Biology in a twist -- deciphering the origins of cell behavior

31.03.2015 | Life Sciences

Wrapping carbon nanotubes in polymers enhances their performance

31.03.2015 | Materials Sciences

Research Links Two Millennia of Cyclones, Floods, El Niño

31.03.2015 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>