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 New technique unveils 'matrix' inside tissues and tumors
29.06.2017 | University of Copenhagen The Faculty of Health and Medical Sciences

nachricht Designed proteins to treat muscular dystrophy
29.06.2017 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making Waves

Computer scientists use wave packet theory to develop realistic, detailed water wave simulations in real time. Their results will be presented at this year’s SIGGRAPH conference.

Think about the last time you were at a lake, river, or the ocean. Remember the ripples of the water, the waves crashing against the rocks, the wake following...

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Nanostructures taste the rainbow

29.06.2017 | Physics and Astronomy

New technique unveils 'matrix' inside tissues and tumors

29.06.2017 | Life Sciences

Cystic fibrosis alters the structure of mucus in airways

29.06.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>