Seemingly invincible cancers stem cells reveal a weakness

June 5, 2014, Whitehead Institute for Biomedical Research

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 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 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 , 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 . 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 to secrete copious amounts of ? It's all very exciting."

Explore further: New breast cancer stem cell findings explain how cancer spreads

More information: "Epithelial-to-mesenchymal transition activates PERK-eIF2a and sensitizes cells to endoplasmic reticulum stress" Cancer Discovery, June, 2014.

Related Stories

New breast cancer stem cell findings explain how cancer spreads

January 14, 2014
Breast cancer stem cells exist in two different states and each state plays a role in how cancer spreads, according to an international collaboration of researchers. Their finding sheds new light on the process that makes ...

New evidence that cancer cells change while moving throughout body

August 12, 2013
For the majority of cancer patients, it's not the primary tumor that is deadly, but the spread or "metastasis" of cancer cells from the primary tumor to secondary locations throughout the body that is the problem. That's ...

Study finds switch that lets early lung cancer grow unchecked

July 11, 2012
Cellular change thought to happen only in late-stage cancers to help tumors spread also occurs in early-stage lung cancer as a way to bypass growth controls, say researchers at Mayo Clinic in Florida. The finding, reported ...

Researchers discover master regulator in cancer metastasis

June 10, 2013
In the process of metastasis, the movement of cancer cells to different parts of the body, a specific master regulator gene plays a central role: a transcription factor named Sox4 activates a sequence of genes and triggers ...

Team highlights new mechanism explaining how cancer cells spread

May 28, 2014
UT Southwestern Medical Center cancer researchers have identified a protein critical to the spread of deadly cancer cells and determined how it works, paving the way for potential use in diagnosis and eventually possible ...

Tracking the cell transitions that cause cancer

March 6, 2013
Researchers think that for cancer to develop, damaged cells have to undergo certain transitions that cause them to spread, or metastasize. Junior Tristan Bepler, a biology and computer science major, is testing this hypothesis, ...

Recommended for you

Study: Cells of three advanced cancers die with drug-like compounds that reverse chemo failure

January 23, 2018
Researchers at Southern Methodist University have discovered three drug-like compounds that successfully reverse chemotherapy failure in three of the most commonly aggressive cancers—ovarian, prostate and breast.

'Hijacker' drives cancer in some patients with high-risk neuroblastoma

January 23, 2018
Researchers have identified mechanisms that drive about 10 percent of high-risk neuroblastoma cases and have used a new approach to show how the cancer genome "hijacks" DNA that regulates other genes. The resulting insights ...

Enzyme inhibitor combined with chemotherapy delays glioblastoma growth

January 23, 2018
In animal experiments, a human-derived glioblastoma significantly regressed when treated with the combination of an experimental enzyme inhibitor and the standard glioblastoma chemotherapy drug, temozolomide.

Scientists block the siren call of two aggressive cancers

January 23, 2018
Aggressive cancers like glioblastoma and metastatic breast cancer have in common a siren call that beckons the bone marrow to send along whatever the tumors need to survive and thrive.

Researchers identify a protein that keeps metastatic breast cancer cells dormant

January 23, 2018
A study headed by ICREA researcher Roger Gomis at the Institute for Research in Biomedicine (IRB Barcelona) has identified the genes involved in the latent asymptomatic state of breast cancer metastases. The work sheds light ...

Boosting cancer therapy with cross-dressed immune cells

January 22, 2018
Researchers at EPFL have created artificial molecules that can help the immune system to recognize and attack cancer tumors. The study is published in Nature Methods.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.