The PDAC Key
Pancreatic cancer cells don’t seem to rely on EMT for metastasis – but it plays a key role in their ability to resist our best chemotherapy options.
At the same time, hundreds of miles away in Houston, a group of researchers from the MD Anderson Cancer Center, Baylor College of Medicine and Rice University were collaborating on a closely related piece of work. Using specialized mouse models of pancreatic cancer with impaired EMT, Raghu Kalluri and his colleagues were investigating the transition’s role in mediating metastasis and chemoresistance. The unexpected conclusion they reached mirrored the one from Dingcheng Gao’s group – namely, that pancreatic cancer, like breast cancer, can metastasize without undergoing EMT (1).
The group began by creating transgenic mouse models of pancreatic ductal adenocarcinoma (PDAC) in which either Snail or Twist, two of the transcription factors responsible for inducing EMT, were knocked out. Deleting the Snai1 and Twist1 genes had no effect on the development or appearance of pancreatic tumors, but the researchers noted a significant decrease in cells undergoing EMT. Immunolabeling of the primary tumor showed far fewer epithelial cells that expressed either αSMA (a mesenchymal marker indicating EMT-positive status) or Zeb1 (another EMT-inducing transcription factor similar to Snail), and global gene expression profiling revealed a decrease in the expression of EMT-associated genes. What was increased, on the other hand, was the degree to which cancer cells proliferated when the transition was suppressed. With no change in the timing of tumorigenesis and local invasion, it’s clear from these experiments that PDAC doesn’t rely on EMT to initiate and progress.
But metastasis is at the heart of the question. Do these cancers rely on EMT in order to spread to distant areas of a mouse’s – or a patient’s – body? The researchers compared circulating tumor cells in control and EMT-suppressed mice and found that the numbers were unchanged. Histopathology and immunostaining in livers, lungs and spleens (the major target organs of metastasis) revealed approximately the same frequency of cancer spreading in both groups – and, when examined more closely, the metastases all proliferated at about the same rate and were largely negative for EMT-inducing factors Twist, Snail, Zeb1 and αSMA. The take-home message? Removing EMT from the equation doesn’t affect the cells’ ability or inclination to metastasize.
So it appears that the Texas group’s pancreatic tumors behave much like the Cornell group’s breast cancers. Is the same true of the cells’ ability to survive chemotherapy? Previous studies have established a link between EMT and gemcitabine resistance in PDAC (2–4). “Gemcitabine works primarily on cancer cells that are dividing or proliferating. When cancer cells suspend their proliferation – such as when they launch an EMT program – then anti-proliferation drugs like gemcitabine do not target them well,” says Kalluri (5). The next step, then, was to test sensitivity to the drug in cells with suppressed EMT. The researchers administered gemcitabine to control, Snail- and Twist-knockout mice and discovered that, with the EMT-inducing factors removed, the chemotherapy-treated animals showed improved histopathology and survival. This held true across different mouse models of pancreatic cancer, all of which showed better responses to gemcitabine after EMT suppression – decreased tumor burden and proliferation, increased cancer cell death, and extended survival times.
“We found that EMT program suppressed drug transporter and concentrative proteins, which inadvertently protected these cancwer cells from anti-proliferative drugs such as gemcitabine,” says Kalluri. “The correlation of decreased survival of pancreatic cancer patients with an increased EMT program is likely due to their impaired capacity to respond to chemotherapy, leading to overall poor prognosis and higher incidence of metastasis.” (5)
Are there other possible explanations? The research still has gaps; it’s possible that other EMT-inducing transcription factors are replacing Snail and Twist in knockout mice, or that EMT suppression from birth (as in the mouse models) has a different effect to EMT suppression only at or after the onset of disease. It doesn’t look like the transition plays a significant role in PDAC metastasis – but in order to make that statement conclusively, more research, and probably more fierce debate amongst researchers, is needed.
But at the moment, the findings are fairly clear with respect to chemoresistance, and it seems clear that – by reducing proliferation and decreasing the expression of genes involved in transporting and concentrating drugs – the transition confers resistance to treatment and thus compromises patient survival. What does that mean for the clinic? Ultimately, that establishing a patient’s EMT status may provide insight into the potential for treatment – and that although treatments targeting the transition may not prevent metastasis, could offer a way of enhancing the effectiveness of existing therapies.
Research Timeline
1995
An overview of epithelio-mesenchymal transition
ED Hay
The EMT produces a mesenchymal tissue type in higher chordates. It’s a central process for embrogenesis. But mesenchymal cells, unlike epithelial ones, can invade and migrate through the extracellular matrix – meaning that EMT has the potential to create invasive metastatic carcinoma cells. E-cadherin gene transfection can convert mesenchymal cells back to epithelial phenotype.
Acta Anat (Basel), 154, 8–20.
2007
Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?
H Peinado et al.
Snail, Zeb and some basic helix-loop-helix (bHLH) factors induce EMT and repress E-cadherin expression. These changes are associated with tumor progression. As a result, further research into these EMT-inducing factors may ultimately have clinical implications, with the potential for targeted treatments that prevent EMT and restore E-cadherin expression.
Nat Rev Cancer, 7, 415–428.
2008
The epithelial–mesenchymal transition generates cells with properties of stem cells
SA Mani et al.
The induction of EMT in human mammary epithelial cells results in the acquisition of not only mesenchymal traits, but also properties associated with stem cells (like increased expression of stem-cell markers or the ability to form mammospheres). Stem-like cells and post-EMT cells exhibit similar behaviors and express similar markers, and post-EMT cells are more efficient at forming mammospheres, colonies and tumors.
Cell, 133, 704–715.
2010
EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer
A Singh, J Settleman
“EMT induction in cancer cells results in the acquisition of invasive and metastatic properties.” The transition can also contribute to the emergence of cancer stem cells and drug resistance. It’s possible that reversible epigenetic changes associated with chemoresistance may depend on the differentiation state of the tumor – and thus on cancer cells’ stem cell-like characteristics or EMT status.
Oncogene, 29, 4741–4751.
2011
Cancer stem cells and epithelial-to-mesenchymal transition (EMT)-phenotypic cells: are they cousins or twins?
D Kong et al.
Cells that have undergone EMT share molecular characteristics with cancer stem cells and are associated with tumor aggressiveness and metastasis. “The acquisition of an EMT phenotype is a critical process for switching early stage carcinomas into invasive malignancies, which is often associated with the loss of epithelial differentiation and gain of mesenchymal phenotype.”
Cancers (Basel), 3, 716–729.
2014
Twist1-induced dissemination preserves epithelial identity and requires E-cadherin
ER Shamir et al.
What are the minimum molecular events necessary to induce the dissemination of epithelial cells? Expression of EMT induction factor Twist1 resulted in rapid dissemination, along with changes to extracellular compartment and cell–matrix (but not cell–cell) adhesion genes. The cells were unexpectedly able to disseminate with membrane-localized β-catenin and E-cadherin (whose knockdown strongly inhibited the process). Therefore, dissemination can occur without loss of the epithelial phenotype – indicating that cancer metastasis might also occur without EMT.
J Cell Biol, 204, 839–856.
Now
Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance
KR Fischer et al.
Nature, 527, 472–476.
Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer
X Zheng et al.
Nature, 527, 525–530.
Cell fate: Transition loses its invasive edge
S Maheswaran, DA Haber
Nature, 527, 452–453.
First published in The Pathologist, a sister publication of The Translational Scientist.
- X Zheng et al., “Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer”, Nature, 527, 525–520 (2015). PMID: 26560028.
- T Yin et al., “Expression of snail in pancreatic cancer promotes metastasis and chemoresistance”, J Surg Res, 141, 196–203 (2007). PMID: 17583745.
- T Arumugam et al., “Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer”, Cancer Res, 69, 5820–5828 (2009). PMID: 19584296.
- K Zhang et al., “Knockdown of snail sensitizes pancreatic cancer cells to chemotherapeutic agents and irradiation”, Int J Mol Sci, 11, 4891–4892 (2010). PMID: 21614180.
- MD Anderson, “Study reveals why chemotherapy may be compromised in patients with pancreatic cancer”, (2015). Available at: bit.ly/1VMjFkh. Accessed April 11, 2016.
While obtaining degrees in biology from the University of Alberta and biochemistry from Penn State College of Medicine, I worked as a freelance science and medical writer. I was able to hone my skills in research, presentation and scientific writing by assembling grants and journal articles, speaking at international conferences, and consulting on topics ranging from medical education to comic book science. As much as I’ve enjoyed designing new bacteria and plausible superheroes, though, I’m more pleased than ever to be at Texere, using my writing and editing skills to create great content for a professional audience.