Metastatic breast cancer cells use hedgehog to 'evilize' docile neighbors

June 12, 2017, CU Anschutz Medical Campus
Heide Ford, PhD, David F. and Margaret Turley Grohne Chair in Basic/Translational Cancer Research, Associate Director for Basic Research at the University of Colorado Cancer Center Credit: University of Colorado Cancer Center

A University of Colorado Cancer Center study published today in Nature Communications shows that metastatic breast cancer cells signal neighboring cells in ways that allow otherwise anchored cells to metastasize. The work pinpoints a promising link in the chain of signaling that, when broken, could reduce the metastatic potential of the disease.

The finding takes place in the context of an important debate in the field of research into breast cancer metastasis, namely whether must undergo what is called epithelial-mesenchymal transition (EMT) in order to metastasize. In EMT, cells that have differentiated to become epithelial tissue (one of the four kinds of specialized tissue in the human body), lose this differentiation to regain characteristics and abilities of . One of these mesenchymal abilities is to survive detachment from anchor tissues to migrate freely to potential new sites of metastasis.

Early work showed that EMT is associated with metastasis. Subsequent work showed that do not, in fact, have to undergo EMT to metastasize (reducing interest in drug development aimed at stopping this transition). However, the current study shows that while individual cells may not have to undergo EMT to metastasize, these non-EMT cells may have to receive signals from cells that have undergone EMT transition, in a process the paper calls, "crosstalk between EMT and non-EMT cells that promotes dissemination."

The paper also pinpoints an important bottleneck for these signals that allow metastasis of otherwise anchored cells: EMT cells signal their non-EMT neighbors by activating the GLI transcription factor. When researchers used the GLI1/2 inhibitor GANT61 to treat models of the disease, non-EMT cells were once again restricted from metastasis.

"A tumor is not one thing. There is heterogeneity - many kinds of cancer cells acting in many different ways. What we show is that within a breast tumor, cells that have undergone EMT that makes them more aggressive and stem-like secrete molecules that affect the behaviors of surrounding cells, making these cells able to navigate the various steps of metastasis and seed new sites. Our work shows that in addition to these cells that have undergone EMT, it may be nearby cells influenced by those EMT cells that are able to metastasize," says Heide Ford, PhD, David F. and Margaret Turley Grohne Chair in Basic/Translational Cancer Research, Associate Director for Basic Research at the University of Colorado Cancer Center.

EMT is induced by a number of chemicals called , which influence the expression of a cell's genes. Previous work in the Ford lab and elsewhere have shown these transcription factors that influence EMT to include Twist1, Snail1 and Six1. The Ford lab has shown that some cancer cells are able to up-regulate these transcription factors, thus increasing the rate of EMT. In the current study, the Ford lab, with first author Deepika Neelakantan, introduced EMT cells expressing these transcription factors to cultures of epithelial breast cancer cells not expressing these transcription factors.

"The addition of cells expressing Snail1 or Twist1 worked through Six1 to increase the migration and invasion of these otherwise more fixed epithelial breast cancer cells," Ford says. Importantly, even the addition of material in which EMT cells had been grown, but without the cells themselves, made cultures of epithelial breast cancer cells more invasive.

"It is not the presence of EMT cells per se that creates the invasive characteristics of epithelial cells," Ford says. "It is the presence of secreted factors created by EMT cells. Although clearly the presence of these EMT cells is the likely source of these secreted factors in tissue."

In other words, some "residue" of EMT cells was gifting the same metastatic potential to non-EMT cells.

The work also shows what this EMT "residue" was doing inside non-EMT, epithelial cells. It turned out that these secreted factors activated the much-studied "" pathway in the epithelial cells, and that this activation was critical to increase the aggressiveness of the epithelial cells.

Again, some breast cancer cells learn to up-regulate transcription factors including Snail1 Twist1, and Six1 to promote EMT, thus gaining the ability to metastasize. Nearby epithelial cells recognize factors secreted by Snail1 and Twist1, again working through Six1, and thus also become able to metastasize. And this signaling takes place through the hedgehog pathway. For the Ford lab the question became where to intercede in the chain of hedgehog signaling to keep these transcription factors from initiating EMT.

This question, as well, exists in the context of an important debate. Hedgehog signaling has been shown to be important in many types of cancer. However, hedgehog inhibitors have been largely unsuccessful in clinical trials. Now with a more precise understanding of how transcription factors interface with the hedgehog pathway to promote EMT and eventually metastasis, the Ford lab hoped to discover exactly where in this chain of hedgehog signaling would be the best place to dam this flow of information.

"The conditions that lead to secretion of these factors are different in different contexts, but eventually it all goes through the main transcription factor that mediates hedgehog signaling, the Gli transcription factor," Ford says. "You can try to break this signaling chain at any point, but we show that breaking the chain at the top of the signaling pathway may not have much effect—EMT cells may still be able to influence through other channels that activate the pathway by targeting Gli in other ways. But because all of this signaling passes through Gli, downstream inhibitors could be efficacious in treating metastatic progression of breast cancer."

Results from this study suggest that the lack of efficacy in hedgehog inhibitors may be due to the pathway becoming activated through different means—targeting any single activation mechanism may not work, as other types of cancer within a heterogeneous population may be able to activate hedgehog in other ways. But downstream from these methods of activation, hedgehog signaling eventually depends on the Gli transcription factor. This study implies that inhibiting hedgehog signaling at the point of Gli transcription factor may help to stop EMT transition and reduce the metastatic potential of breast .

Explore further: Breast cancer stem cells radicalize normal neighbors for purpose of metastasis

More information: Deepika Neelakantan et al, EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells, Nature Communications (2017). DOI: 10.1038/ncomms15773

Related Stories

Breast cancer stem cells radicalize normal neighbors for purpose of metastasis

April 18, 2016
A University of Colorado Cancer Center study presented at the American Association for Cancer Research Annual Meeting 2016 shows that stem-like breast cancer cells secrete molecules that allow neighboring, otherwise anchored ...

Scientists use modelling to show the role of metabolism and signaling in cancer metastasis

June 7, 2016
Researchers have built a model to investigate the metastasis of cancer by examining the metabolism of breast epithelial cells and look at the role of signaling. This research, published in PLOS Computational Biology, may ...

Hedgehog signaling pathway for breast cancer identified

November 13, 2014
Molecules called long non-coding RNAs (lncRNAs) have been implicated in breast cancer but exactly why they cause metastasis and tumor growth has been little understood...until now.

Diabetes drug may be effective against deadly form of breast cancer, study suggests

March 7, 2017
Researchers in China have discovered that a metabolic enzyme called AKR1B1 drives an aggressive type of breast cancer. The study, "AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates ...

Looking beyond cancer cells to understand what makes breast cancer spread

February 16, 2017
To understand what makes breast cancer spread, researchers are looking at where it lives - not just its original home in the breast but its new home where it settles in other organs. What's happening in that metastatic niche ...

New signaling pathway linked to breast cancer metastasis

April 2, 2012
Lymph nodes help to fight off infections by producing immune cells and filtering foreign materials from the body, such as bacteria or cancer cells. Thus, one of the first places that cancer cells are found when they leave ...

Recommended for you

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

Researchers develop swallowable test to detect pre-cancerous Barrett's esophagus

January 17, 2018
Investigators at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center have developed a simple, swallowable test for early detection of Barrett's esophagus that offers promise ...

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.

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.