Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 6, Pages 2078-2083Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1120605109
Keywords
Boolean analysis; stem and progenitor cells; biomarker; cancer stem cell; systems biology
Categories
Funding
- Deutsche Forschungsgemeinschaft [VO 1704/1-1]
- Urologisch Wissenschaftliche Gesellschaft
- National Institutes of Health (NIH) [K99CA151673-01A1, P01CA139490]
- Department of Defense [W81XWH-10-1-0500]
- Siebel Stem Cell Institute
- Thomas and Stacey Siebel Foundation
- Radiological Society of North America [RR0832, RR0907]
- Howard Hughes Medical Institute
- Stanford Medical Scholar Program
- Lacob Program of Excellence in Gynecologic-Ovarian Cancer Research and Treatment
- California Institute of Regerenative Medicine [TB1-01190]
- Ludwig Institute
- Jim and Carolyn Pride Family Fund
- Smith Family Foundation
- National Cancer Institute [R00CA129640-04]
- V Foundation for Cancer Research
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Current clinical judgment in bladder cancer (BC) relies primarily on pathological stage and grade. We investigated whether a molecular classification of tumor cell differentiation, based on a developmental biology approach, can provide additional prognostic information. Exploiting large preexisting gene-expression databases, we developed a biologically supervised computational model to predict markers that correspond with BC differentiation. To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population.
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