Three differentiation states risk-stratify bladder cancer into distinct subtypes

Abstract

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.

Natural killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells

“…3 Urology and Renal Transplantation Department, Coimbra University Hospital Centre (CHUC), Coimbra, Portugal. 4 Institute of Immunology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.…”

“…Although the majority of the newly diagnosed cases are non-muscle-invasive tumors (NMIBC), up to 80 % recur and a significant part progresses to therapy refractory muscle-invasive forms (MIBC) [3,4].…”

Stage- and subunit-specific functions of polycomb repressive complex 2 in bladder urothelial formation and regeneration

“…Papafotiou et al (2016) show that Krt14 expression marks a subpopulation of murine bladder basal cells with essential roles in regeneration and tumorigenesis. Expression of KRT14 is also linked to human bladder cancer development (Cancer Genome Atlas Research Network, 2014;Sjodahl et al, 2012;Volkmer et al, 2012). Interestingly, the Krt14 + as well as the ectopic Krt17 + subpopulations of basal cells are significantly increased in Eed mutants.…”

CD14-expressing cancer cells establish the inflammatory and proliferative tumor microenvironment in bladder cancer

“…We have previously determined that keratin 14 (KRT14) expression marks the most primitive differentiation state in BC cells (32). KRT14 expression is significantly associated with poor overall patient survival.…”