Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Seemingly invincible cancers stem cells reveal a weakness


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:

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

More articles from Life Sciences:

nachricht Two decades of training students and experts in tracking infectious disease
27.11.2015 | Hochschule für Angewandte Wissenschaften Hamburg

nachricht Increased carbon dioxide enhances plankton growth, opposite of what was expected
27.11.2015 | Bigelow Laboratory for Ocean Sciences

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Climate study finds evidence of global shift in the 1980s

Planet Earth experienced a global climate shift in the late 1980s on an unprecedented scale, fuelled by anthropogenic warming and a volcanic eruption, according to new research published this week.

Scientists say that a major step change, or ‘regime shift’, in the Earth’s biophysical systems, from the upper atmosphere to the depths of the ocean and from...

Im Focus: Innovative Photovoltaics – from the Lab to the Façade

Fraunhofer ISE Demonstrates New Cell and Module Technologies on its Outer Building Façade

The Fraunhofer Institute for Solar Energy Systems ISE has installed 70 photovoltaic modules on the outer façade of one of its lab buildings. The modules were...

Im Focus: Lactate for Brain Energy

Nerve cells cover their high energy demand with glucose and lactate. Scientists of the University of Zurich now provide new support for this. They show for the first time in the intact mouse brain evidence for an exchange of lactate between different brain cells. With this study they were able to confirm a 20-year old hypothesis.

In comparison to other organs, the human brain has the highest energy requirements. The supply of energy for nerve cells and the particular role of lactic acid...

Im Focus: Laser process simulation available as app for first time

In laser material processing, the simulation of processes has made great strides over the past few years. Today, the software can predict relatively well what will happen on the workpiece. Unfortunately, it is also highly complex and requires a lot of computing time. Thanks to clever simplification, experts from Fraunhofer ILT are now able to offer the first-ever simulation software that calculates processes in real time and also runs on tablet computers and smartphones. The fast software enables users to do without expensive experiments and to find optimum process parameters even more effectively.

Before now, the reliable simulation of laser processes was a job for experts. Armed with sophisticated software packages and after many hours on computer...

Im Focus: Quantum Simulation: A Better Understanding of Magnetism

Heidelberg physicists use ultracold atoms to imitate the behaviour of electrons in a solid

Researchers at Heidelberg University have devised a new way to study the phenomenon of magnetism. Using ultracold atoms at near absolute zero, they prepared a...

All Focus news of the innovation-report >>>



Event News

Fraunhofer’s Urban Futures Conference: 2 days in the city of the future

25.11.2015 | Event News

Gluten oder nicht Gluten? Überempfindlichkeit auf Weizen kann unterschiedliche Ursachen haben

17.11.2015 | Event News

Art Collection Deutsche Börse zeigt Ausstellung „Traces of Disorder“

21.10.2015 | Event News

Latest News

Siemens to supply 126 megawatts to onshore wind power plants in Scotland

27.11.2015 | Press release

Two decades of training students and experts in tracking infectious disease

27.11.2015 | Life Sciences

Coming to a monitor near you: A defect-free, molecule-thick film

27.11.2015 | Materials Sciences

More VideoLinks >>>