Cancer stem cells (CSC) have been identified in an increasing number of human malignancies, and their enhanced growth potential has suggested that they play a major role in disease initiation, maintenance, relapse and progression. We hypothesize that better understanding CSCs will ultimately improve long-term clinical outcomes and have begun to study CSC in pancreatic adenocarcinoma, a leading cause of cancer deaths. We have found that pancreatic cancer cells with increased tumorigenic potential express aldehyde dehydrogenase (ALDH), a detoxifying enzyme expressed by many normal stem cells. Moreover, ALDH+ cells express genes consistent with the epithelial-mesenchymal transition and are more invasive and migratory when compared to bulk tumor cells. We have also compared ALDH+ cells with CD44+CD24+ cells that have also been identified by others as pancreatic CSC and found that each phenotype marks distinct cell populations that are largely non- overlapping. Interestingly, each CSC population is equally capable of forming tumors, but ALDH+ cells are often more migratory and invasive. Based on these findings, we hypothesize that individual tumors contain distinct CSC populations that may or may not share specific functional properties. Moreover, these findings suggest that CSCs may vary amongst pancreatic tumors from different patients depending on their specific genetic mutations or stage of disease. Since the development of CSC targeting strategies requires their precise identification, it is imperative that the relationship between their phenotype and functional properties and the factors that influence this relationship are better understood. Moreover, it is likely that extracellular signals within the tumor microenvironment regulate CSC properties, but this is also poorly understood. We propose to address these questions and will: (1) Define the relationship between distinct CSC populations in pancreatic cancer;(2) Examine the cellular diversity of pancreatic CSC;and (3) Determine whether interactions between pancreatic CSCs and the extracellular matrix can serve as novel CSC targeting strategies.

Public Health Relevance

Several groups have identified pancreatic cancer stem cells with the increased tumorigenic and metastatic potential. We will determine whether these cells differ amongst individual patients and regulated by the tumor environment. These findings may improve the treatment and survival of patients with pancreatic carcinoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA150142-02
Application #
8332790
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Thurin, Magdalena
Project Start
2011-09-14
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$341,433
Indirect Cost
$128,354
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Bailey, Jennifer M; Alsina, Janivette; Rasheed, Zeshaan A et al. (2014) DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology 146:245-56
Ghiaur, Gabriel; Gerber, Jonathan M; Matsui, William et al. (2012) Cancer stem cells: relevance to clinical transplantation. Curr Opin Oncol 24:170-5