2017.07.22 08:29
JULY 17, 2017
Blood test for early detection of pancreatic cancer headed to clinic
Penn Medicine News
A newly identified biomarker panel could pave the way to earlier detection and better treatment for pancreatic cancer, according to new research from the Perelman School of Medicine at University of Pennsylvania. Currently over 53,000 people in the United States are diagnosed with pancreatic cancer – the fourth leading cause of cancer death – every year. The blood biomarkers, detailed in the journal Science Translational Medicine, correctly detected pancreatic cancer in blood samples from patients at different stages of their disease.
The majority of pancreatic cancer patients are not diagnosed until an advanced stage, beyond the point at which their tumors can be surgically removed.
A team led by Ken Zaret, PhD, director of the Penn Institute for Regenerative Medicine and the Joseph Leidy Professor of Cell and Developmental Biology, and Gloria Petersen, PhD, from the Mayo Clinic, identified a pair of biomarkers that physicians could soon use to discover the disease earlier. “Starting with our cell model that mimics human pancreatic cancer progression, we identified released proteins, then tested and validated a subset of these proteins as potential plasma biomarkers of this cancer,” Zaret said. The authors anticipate that health care providers will use the early–detection biomarkers to test for their presence and levels in blood from pancreatic cancer patients and blood drawn from individuals with a high risk of developing pancreatic cancer, including those who have a first–degree relative with pancreatic cancer, are genetically predisposed to the disease, or who had a sudden onset of diabetes after the age of 50.
“Early detection of cancer has had a critical influence on lessening the impact of many types of cancer, including breast, colon, and cervical cancer. A long standing concern has been that patients with pancreatic cancer are often not diagnosed until it is too late for the best chance at effective treatment,” said Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center (ACC) at the University of Pennsylvania. “Having a biomarker test for this disease could dramatically alter the outlook for these patients.”
The biomarker panel, enabled by discovery work of first author Jungsun Kim, PhD, a postdoctoral fellow in Zaret’s lab, builds on a first–of–its–kind human–cell model of pancreatic cancer progression the lab described in 2013. They used stem–cell technology to create a cell line from a patient with advanced pancreatic ductal adenocarcinoma. Genetically reprogramming late–stage human cancer cells to a stem–cell state enabled them to force the reprogrammed cells to progress to an early cancerous state, revealing secreted blood biomarkers of early–stage disease along the way. The best candidate biomarker, plasma thrombospondin–2 (THBS2), was screened against 746 cancer and control plasma samples using an inexpensive, commercially available protein–detection assay. The team found that blood levels of THBS2, combined with levels of a known later–stage biomarker called CA19–9, was reliable at detecting the presence of pancreatic cancer in patients.
The team refined the assay with independent investigations of plasma samples from patients with different stages of cancer, from individuals with benign pancreatic disease, and from healthy controls, all obtained from Petersen, who directs the biospecimen resource program for pancreas research at the Mayo Clinic.
“Positive results for THBS2 or CA19–9 concentrations in the blood consistently and correctly identified all stages of the cancer,” Zaret said. “Notably, THBS2 concentrations combined with CA19–9 identified early stages better than any other known method.” The combination panel also improved the ability to distinguish cases of cancer from pancreatitis. The panel will next be validated in a setYou
2017.07.22 08:42
2017.07.22 08:48
Pancreatic cancer carries a dismal prognosis. According to the National Cancer Institute, the overall five-year relative survival for 2003-2009 was 6 percent.
Still, researchers and clinicians don't have a non-invasive way to even detect early cells that portent later disease. 'There's no PSA test for pancreatic cancer,' they say, and that's one of the main reasons why pancreatic cancer is detected so late in its course. They have been searching for a human-cell model of early-disease progression. Now, Perelman School of Medicine, University of Pennsylvania scientists have used stem-cell technology to create a research cell line from a patient with advanced pancreatic ductal adenocarcinoma (PDAC).
This first-of-its-kind human-cell model of pancreatic cancer progression was published this week in Cell Reports from the lab of Ken Zaret, PhD, professor of Cell and Developmental Biology.
"It is the first example using induced pluripotent stem [iPS] cells to model cancer progression directly from a solid tumor, and the first human cell line that can model pancreatic cancer progression from early to invasive stages," says Zaret, also the associate director of the Penn Institute for Regenerative Medicine.
"We were able to predict the appearance of cellular features and protein markers in the intermediate stages of pancreatic cancer that are not evident in the terminal stages. This has given us new perspectives into what this deadly type of cancer looks like -- something no one has seen before in human cells. Our analysis revealed known molecular networks that are activated during PDAC progression, as well as a new molecular network that is activated during the intermediate stages. This could provide a fresh outlook on biomarkers for early stages of the disease."
A Leap of Faith
Zaret and first author Jungsun Kim, PhD, a postdoctoral associate in the Zaret lab, hypothesized that if human PDAC cells were reprogrammed back to pluripotent cells and then allowed to re-differentiate into pancreatic tissue, they might undergo the early stages of cancer. To do this, they created the PDAC pluripotent cells and indeed found that they recapitulated the early to intermediate stages of pancreatic cancer. They then isolated the cells at the early stage, cultured the cells in vitro, and identified the secreted and released proteins that might serve as early-stage biomarkers of disease progression.
There's one caveat, though, says Zaret. "Using the iPS method, we could only get a cancer cell line from one patient to reprogram, meaning this work is representative of one individual's cancer," noting that his close collaboration with John Hoffman, a surgeon from the Fox Chase Cancer Center (FCCC) was key in order to get fresh cancer cells for the reprogramming. They tried this method with cells from nine human tumors in total. However, as Zaret points out, there are many examples of where a single human cell line has served as a highly useful model for human disease.
"Our iPS-like cells exhibited pluripotency, like other stem cells, but when they differentiated after we injected them into the immunodeficient mice, they preferentially developed into early-stage pancreatic cancer cells," says Zaret. He explains that the approach is another example of using iPS cells from human patients to model disease, by capturing the genome of an affected individual. However, this is a first in solid tumor cancers, whereas many other labs have developed these types of cell lines for neurological and cardiovascular disorders.
The visual characteristics of these cancer cells -- as they progress from early- to late-stage cancer -- are typical of what is seen in cells analyzed from cancer patients in the clinic now. In the early stage, pancreatic ducts have lesions with cells of an abnormal shape, and express characteristic proteins as measured by stains. Over time, some of these aberrant cells may grow excessively, lose their ductal characteristics, and become invasive.
When the human PDAC iPS cells are grown as lesions in the mouse, they secrete or release proteins corresponding to protein networks expressed during the progression of human pancreatic cancer, namely molecules centered on a trio of key proteins: HNF4, integrin, and TGFbeta.
"We propose to look in the blood of potential pancreatic cancer patients or relatively early-stage patients for the biomarkers we found downstream of these molecular networks, to see if they are present in people," says Zaret.
The Making of a Model
This approach allows human cells to be studied directly, as opposed to examining characteristics of pancreatic cancer progression in an animal model and then having to assess whether the findings apply to humans. The cells harvested from the cancer patient were reprogrammed using the four Yamanaka factors carried in a lentivirus, which was adapted by the Zaret lab.
To see what the reprogramming did at a genetic level, the team compared the genomic structure of the early iPS pancreatic cancer cell line to original tumor cells from which the cell line was isolated. They found 23 chromosomal aberrations in the primary tumor cells as compared to 20 of the same chromosomal aberrations in the PDAC iPS line, demonstrating that the PDAC iPS line was derived from the original tumor cells.
By contrast, no chromosomal abberations were seen in cells taken from the margin of the tumor in a cancer-free part of the pancreas from the patient, as well as from an iPS line that the Zaret group made from the margin cells.
These sets of comparisons allowed the team to directly observe the changes in the pancreatic cancer cell line versus a normal cell line derived from the same human genetic background.
"We understand that the pancreatic cancer field has been dogged by searching for unique markers in the blood that detect disease early, and we hope that this live-cell progression approach will gives us a new way to see early molecular markers for pancreatic cancer," says Zaret.
"Since we can detect released protein markers of at least three different networks from the early-stage human lesions in our model, we think that looking for blood markers of the simultaneous activation the three pathways, instead of a single marker, could provide better leverage in detection. The new model could also be used to test drugs that block the intermediate stages of the disease. We would also like to know how we got lucky with this one cell line, so that the iPS technology can be adapted to model other human cancers." The research was funded by the National Institute for General Medical Sciences through an NIH Merit award (R37GM36477)
Other co-authors are R. Katherine Alpaugh, Andrew D. Rhim, Maximilian Reichert, Ben Z. Stanger, Emma E. Furth, Antonia R. Sepulveda, Chao-Xing Yuan, Kyoung-Jae Won, Greg Donahue, and Jessica Sands, all from Penn, and Andrew A. Gumbs, from FCCC.
Story Source:
Materials provided by Perelman School of Medicine at the University of Pennsylvania. Note: Content may be edited for style and length.
2017.07.22 11:15
RESEARCH ARTICLECANCER
Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers
+ See all authors and affiliations
Science Translational Medicine 12 Jul 2017:
Vol. 9, Issue 398, eaah5583
DOI: 10.1126/scitranslmed.aah5583
2017.07.22 11:25
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The above news is per 김건언(65), which I received just now..
Jungsun Kim, PhD, postdoctoral fellow at Dr. Zaret's lab, is credited
to the discovery of these biomarkers.
She received her PhD from 한양대학교.