First human model of PDAC progression via pluripotent stem cells

An induced pluripotent stem cell line was created from human pancreatic ductal adenocarcinoma (PDAC), providing researchers with the first human-cell model of the early-disease progression of pancreatic cancer.

"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," said senior author Ken Zaret, PhD, of the University of Pennsylvania School of Medicine in Philadelphia. This study was published in Cell Reports (2013; doi:10.1016/j.celrep.2013.05.036).

"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,” said Zaret. “Our analysis revealed known molecular networks that are activated during PDAC [pancreatic ductal adenocarcinoma] 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."

The research team hypothesized that if human cells from a patient with advanced pancreatic ductal adenocarcinoma were reprogrammed back to pluripotent cells and then allowed to re-differentiate into pancreatic tissue, they might undergo the early stages of cancer. Though the team tried with cells from nine human tumors in total, only one cell line from one patient was successfully reprogramed to create the PDAC pluripotent cells.

The PDAC pluripotent cells did recapitulate the early to intermediate stages of pancreatic cancer. Next, the researchers isolated the cells at the early stage, cultured the cells in vitro, and identified the proteins that were secreted and released, since these could serve as early-stage biomarkers of disease progression.

When the human PDAC iPS cells were grown as lesions in mice, they released or secreted proteins that correspond to protein networks expressed during the progression of human pancreatic cancer. These molecules center 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," said Zaret.
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