Single-cell transcription site activation predicts chemotherapy response in human colorectal tumors

Rossanna C. Pezo, Saumil J. Gandhi, L. Andrew Shirley, Richard G. Pestell, Leonard H. Augenlicht, Robert H. Singer

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Candidate gene and pathway approaches, and unbiased gene expression profiling, have identified marker signatures predictive of tumor phenotypes, such as drug sensitivity and invasive or metastatic potential. However, application of such information to evaluation of tumors in the clinic is limited by cell heterogeneity in the tumor. We have developed a novel method of fluorescence in situ hybridization (FISH) that can detect transcriptional activation of individual genes at their site in single cells in the interphase nucleus. A major obstacle in the treatment of colorectal cancer is relative insensitivity to the chemotherapeutic agent 5-Fluorouracil (5-FU). Here, we have developed a sensitive approach to predict relative sensitivity of colorectal cancer cells to 5-FU, using FISH with probes targeted to nascent mRNAs to measure the number of individual cells with active transcription sites for a panel of candidate genes. These results reveal that the transcriptional status of four key genes, thymidylate synthase (TYMS), MORFrelated gene X (MRGX), Bcl2-antagonist/killer (BAK), and ATPase, Cu2+ transporting β polypeptide (ATP7B), can accurately predict response to 5-FU. As proof of principle, we show that this transcriptional profile is predictive of response to 5-FU in a small number of patient colon tumor tissues. This approach provides a novel ability to identify and characterize unique minor cell populations in the tumor that may exhibit relative resistance to chemotherapy.

Original languageEnglish (US)
Pages (from-to)4977-4982
Number of pages6
JournalCancer Research
Volume68
Issue number13
DOIs
StatePublished - Jul 1 2008

Fingerprint

Transcriptional Activation
Colorectal Neoplasms
Fluorouracil
Drug Therapy
Genes
Neoplasms
Fluorescence In Situ Hybridization
Thymidylate Synthase
Interphase
Gene Expression Profiling
Adenosine Triphosphatases
Catalytic Domain
Colon
Cell Count
Phenotype
Messenger RNA
Peptides
Pharmaceutical Preparations
Population
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Single-cell transcription site activation predicts chemotherapy response in human colorectal tumors. / Pezo, Rossanna C.; Gandhi, Saumil J.; Shirley, L. Andrew; Pestell, Richard G.; Augenlicht, Leonard H.; Singer, Robert H.

In: Cancer Research, Vol. 68, No. 13, 01.07.2008, p. 4977-4982.

Research output: Contribution to journalArticle

Pezo, Rossanna C. ; Gandhi, Saumil J. ; Shirley, L. Andrew ; Pestell, Richard G. ; Augenlicht, Leonard H. ; Singer, Robert H. / Single-cell transcription site activation predicts chemotherapy response in human colorectal tumors. In: Cancer Research. 2008 ; Vol. 68, No. 13. pp. 4977-4982.
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