Analysis of the tumor-initiating and metastatic capacity of PDX1-positive cells from the adult pancreas
Authors
Irene Ischenko, Oleksi Petrenko, and Michael J. Hayman
Institution
Stony Brook
Country
United States
Year
2014
Journal
PNAS
Abstract
Pancreatic cancer is one of the deadliest human malignancies.
A striking feature of pancreatic cancer is that activating Kras
mutations are found in ∼90% of cases. However, apart from a restricted
population of cells expressing pancreatic and duodenal
homeobox 1 (PDX1), most pancreatic cells are refractory to Krasdriven
transformation. In the present study, we sought to determine
which subsets of PDX1+ cells may be responsible for tumor
growth. Using the Lox-Stop-Lox–KrasG12D genetic mouse model
of pancreatic carcinogenesis, we isolated a population of
KrasG12D-expressing PDX1+ cells with an inherent capacity to
metastasize. This population of cells bears the surface phenotype
of EpCAM+CD24+CD44+CD133–SCA1− and is closer in its properties
to stem-like cells than to more mature cell types. We further
demonstrate that the tumorigenic capacity of PDX1+ cells is limited,
becoming progressively lost as the cells acquire a mature
phenotype. These data are consistent with the hypothesis that
the adult pancreas harbors a dormant progenitor cell population
that is capable of initiating tumor growth under conditions of
oncogenic stimulation. We present evidence that constitutive activation
of the mitogen-activated protein kinase (MAPK/ERK) signaling
and stabilization of the MYC protein are the two main
driving forces behind the development of pancreatic cancer cells
with stem-cell–like properties and high metastatic potential. Our
results suggest that pancreatic cells bearing Kras mutation can be
induced to differentiate into quasi-normal cells with suppressed
tumorigenicity by selective inhibition of the MAPK/ERK/MYC
signaling cascade.