Clinical recurrence after therapy with cytotoxic agents presents a life threatening problem for a large number of cancer patients. It has been hypothesized that this form of therapy resistance is mediated by a small population of growth arrested cancer stem cells that survive treatment and initiate recurrence. Although intriguing, this hypothesis remains untested due to technical limitations that preclude direct detection of these growth arrested cancer cells within intact tumors. We have overcome this problem with the development of a dual fluorescent reporter system that permanently marks all cancer cells with the expression of a red fluorescent protein, while it distinguishes slow-cycling from rapidly proliferating cancer cells by their retention of a doxycycline repressible Histone 2B green fluorescent fusion protein (H2BGFP) in pulse-chase experiments. Using squamous cell carcinoma as a paradigm for hierarchically organized tumors, we are able to detect fast cycling and growth arrested cancer cells with tumor initiating potential. This application aims to test the hypothesis that: (1.) squamous cell carcinomas contain cancer stem cells that interconvert between fast and slow cycling states by responsive adaptation mechanisms; (2.) fast and slow cycling cancer stem cells are defined by characteristic molecular signatures that govern their proliferative behavior; and (3.) slow cycling cancer stem cells are inert to cytotoxic drugs and able to initiate recurrence after treatment. The results of our research are expected to positively impact the design of therapies and treatment of cancer patients as the identification of quiescent cancer stem cells and the mechanisms that govern their behavior presents a first step towards the identification of prognostic markers that predict which cancers will resist cytotoxic therapies It will also promote the development of novel combination therapies that specifically stimulate proliferation of quiescent cancer stem cells to increase their vulnerability to cytotoxic drugs, without affecting quiescence of normal, adult stem cells.

Public Health Relevance

A widely accepted but experimentally untested hypothesis posits that therapy resistant cancers contain growth arrested cells with tumor initiating potential The identity of these cells and their molecular signatures are currently unknown. Our novel experimental approach, outlined in this application, will allow us for the first time to identify ad characterize these growth arrested and therapy resistant cancer cells in their native environment within intact tumors. The results of our research are expected to identify tumors that are likely to recur following standard treatments, and lead to the development of specific therapies to target these cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA181111-02
Application #
8776932
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Mohla, Suresh
Project Start
2013-12-01
Project End
2018-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
2
Fiscal Year
2015
Total Cost
$316,541
Indirect Cost
$129,791
Name
New York University
Department
Dermatology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Xiong, Xiaozhong; Schober, Markus; Tassone, Evelyne et al. (2018) KLF4, A Gene Regulating Prostate Stem Cell Homeostasis, Is a Barrier to Malignant Progression and Predictor of Good Prognosis in Prostate Cancer. Cell Rep 25:3006-3020.e7
Brown, Jessie A; Schober, Markus (2018) Cellular quiescence: How TGF? protects cancer cells from chemotherapy. Mol Cell Oncol 5:e1413495
Brown, Jessie A; Yonekubo, Yoshiya; Hanson, Nicole et al. (2017) TGF-?-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma. Cell Stem Cell 21:650-664.e8
Brown, Jessie A; Schober, Markus (2017) Joining Forces: Bmi1 Inhibition and Cisplatin Curb Squamous Carcinogenesis. Cell Stem Cell 20:575-577