Preventing pancreatic cancer metastasis by keeping cells 'sheltered in
place'

Date:
June 8, 2020
Source:
Sanford Burnham Prebys Medical Discovery Institute
Summary:
Scientists have shown that pancreatic cancer metastasis -- when
tumor cells gain the deadly ability to migrate to new parts of the
body -- can be suppressed by inhibiting a protein called Slug that
regulates cell movement. The study also revealed two druggable
targets that interact with Slug and hold promise as treatments
that may stop the spread of pancreatic cancer.



FULL STORY ========================================================================== Scientists at Sanford Burnham Prebys Medical Discovery Institute have
shown that pancreatic cancer metastasis -- when tumor cells gain the
deadly ability to migrate to new parts of the body -- can be suppressed by inhibiting a protein called Slug that regulates cell movement. The study, published in the Journal of Experimental Medicine, also revealed two
druggable targets that interact with Slug and hold promise as treatments
that may stop the spread of pancreatic cancer.


========================================================================== "Pancreatic cancer cells are notorious for their ability to escape from
a tumor. Even when pancreatic cancer is caught early, tumor cells are
already found circulating throughout the body," says Cosimo Commisso,
Ph.D., an associate professor in Sanford Burnham Prebys' NCI-designated
Cancer Center and senior study author. "Our study suggests that we may
be able to create treatments that stop pancreatic cancer cells from
untethering in the first place, which could reduce metastasis and help
more people survive this deadly cancer." Stopping the migration of
hungry cancer cells Pancreatic cancer cells, like all cancer cells,
grow rapidly and quickly deplete the nutrients in their surrounding environment. To meet their energy needs, tumor cells boost metabolic
pathways that normal cells don't use.

Commisso is working to understand how pancreatic cancer cells respond to nutrient deprivation -- focusing on the most commonly depleted nutrient, glutamine -- with the goal of finding treatments that stop the growth
of cancer cells without harming healthy cells.

In the study, the scientists used a mouse model of pancreatic cancer to
show that, in response to glutamine deficiency, a protein called Slug
drives metastasis by activating the epithelial-mesenchymal transition,
or EMT -- the process cells use to free themselves from tightly packed
tissue. Inhibiting Slug reduced the cancer's ability to spread --
demonstrated by a reduction in the number and size of secondary lung
tumors. The scientists also established that patient samples with higher
levels of Slug were linked to a poor prognosis -- further indicating
that blocking the protein may be beneficial.

"The field of pancreatic cancer research is still working to understand
the role of EMT in metastasis. Our study shows that glutamine deficiency
indeed activates EMT, through Slug, to allow pancreatic cancer cells
to escape and look for nutrient-rich grounds," says Maria Victoria
Recouvreux, Ph.D., a staff scientist in the Commisso lab at Sanford
Burnham Prebys and the first author of the study. "In addition to
revealing new therapeutic avenues that may halt pancreatic cancer
metastasis, these findings might also apply to other tumors that rapidly consume glutamine, including lung and colon cancers." Because Slug
is considered "undruggable" due to inherent biological properties,
the scientists continued to search for proteins that interact with
Slug and could be targeted with a drug. Their research identified two
promising targets: ERK and eIF2 alpha. ERK inhibitors are currently
under evaluation in clinical trials for pancreatic and other cancers;
and an eIF2 alpha inhibitor has completed animal testing.

New hope for a deadly cancer Once pancreatic cancer metastasizes, the
number of people who are alive five years later drops from 37% to only
3%. Of the 57,000 Americans expected to be diagnosed with pancreatic
cancer in 2020, about 10% are diagnosed at an early stage and may
benefit from a drug that prevents metastasis. For unknown reasons,
pancreatic cancer is on the rise and predicted to become the second-
leading cause of cancer-related deaths in the U.S.

Now that the researchers have established the important role of Slug in
driving metastatic pancreatic cancer, they plan to expand their research
to determine Slug's role in pancreatic cancer overall, including impact
on disease aggressiveness and survival.

"To make progress in the fight against pancreatic cancer, it is critical
that we have a strong scientific understanding of what is driving the
tumor's growth and metastasis," says Lynn Matrisian, Ph.D., chief science officer at the Pancreatic Cancer Action Network (PanCAN), who wasn't
involved in the study.

"Today's findings reveal new insights into how pancreatic cancer
metastasizes, providing both hope and important new directions for
research that might be able to help more people survive the world's
toughest cancer."

========================================================================== Story Source: Materials provided by Sanford_Burnham_Prebys_Medical_Discovery_Institute. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Cosimo Commisso, Anindya Bagchi, Andrew Lowy, Yijuan Zhang,
Brian James,
Michael Jung, Koen M.O. Galenkamp, Matthew R. Moldenhauer, Maria
Victoria Recouvreux. Glutamine depletion regulates Slug to promote
EMT and metastasis in pancreatic cancer. Journal of Experimental
Medicine, 2020; 217 (9) DOI: 10.1084/jem.20200388 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200608092958.htm

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