Loss of stromal IMP1 promotes a tumorigenic microenvironment in the colon

Kathryn E. Hamilton, Priya Chatterji, Emma T. Lundsmith, Sarah F. Andres, Veronique Giroux, Philip D. Hicks, Felicite K. Noubissi, Vladimir Spiegelman, Anil K. Rustgi

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The colon tumor microenvironment is becoming increasingly recognized as a complex but central player in the development of many cancers. Previously, we identified an oncogenic role for the mRNA-binding protein IMP1 (IGF2BP1) in the epithelium during colon tumorigenesis. In the current study, we reveal the contribution of stromal IMP1 in the context of colitis-associated colon tumorigenesis. Interestingly, stromal deletion of Imp1 (Dermo1Cre;Imp1LoxP/LoxP, or Imp1δMes) in the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated cancer resulted in increased tumor numbers of larger size and more advanced histologic grade than controls. In addition, Imp1 δMes mice exhibited a global increase in protumorigenic microenvironment factors, including enhanced inflammation and stromal components. Evaluation of purified mesenchyme from AOM/DSS-treated Imp1δMes mice demonstrated an increase in hepatocyte growth factor (HGF), which has not been associated with regulation via IMP1. Genetic knockdown of Imp1 in human primary fibroblasts confirmed an increase in HGF with Imp1 loss, demonstrating a specific, cell-autonomous role for Imp1 loss to increase HGF expression. Taken together, these data demonstrate a novel tumor-suppressive role for IMP1 in colon stromal cells and underscore an exquisite, context-specific function for mRNA-binding proteins, such as IMP1, in disease states. Implications: The tumor-suppressive role of stromal IMP1 and its ability to modulate protumorigenic factors suggest that IMP1 status is important for the initiation and growth of epithelial tumors.

Original languageEnglish (US)
Pages (from-to)1478-1486
Number of pages9
JournalMolecular Cancer Research
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2015

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Colon
Hepatocyte Growth Factor
Azoxymethane
Neoplasms
Dextran Sulfate
Colitis
Carrier Proteins
Carcinogenesis
Messenger RNA
Tumor Microenvironment
Mesoderm
Stromal Cells
Epithelium
Fibroblasts
Inflammation
Growth

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Hamilton, K. E., Chatterji, P., Lundsmith, E. T., Andres, S. F., Giroux, V., Hicks, P. D., ... Rustgi, A. K. (2015). Loss of stromal IMP1 promotes a tumorigenic microenvironment in the colon. Molecular Cancer Research, 13(11), 1478-1486. https://doi.org/10.1158/1541-7786.MCR-15-0224
Hamilton, Kathryn E. ; Chatterji, Priya ; Lundsmith, Emma T. ; Andres, Sarah F. ; Giroux, Veronique ; Hicks, Philip D. ; Noubissi, Felicite K. ; Spiegelman, Vladimir ; Rustgi, Anil K. / Loss of stromal IMP1 promotes a tumorigenic microenvironment in the colon. In: Molecular Cancer Research. 2015 ; Vol. 13, No. 11. pp. 1478-1486.
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Hamilton, KE, Chatterji, P, Lundsmith, ET, Andres, SF, Giroux, V, Hicks, PD, Noubissi, FK, Spiegelman, V & Rustgi, AK 2015, 'Loss of stromal IMP1 promotes a tumorigenic microenvironment in the colon', Molecular Cancer Research, vol. 13, no. 11, pp. 1478-1486. https://doi.org/10.1158/1541-7786.MCR-15-0224

Loss of stromal IMP1 promotes a tumorigenic microenvironment in the colon. / Hamilton, Kathryn E.; Chatterji, Priya; Lundsmith, Emma T.; Andres, Sarah F.; Giroux, Veronique; Hicks, Philip D.; Noubissi, Felicite K.; Spiegelman, Vladimir; Rustgi, Anil K.

In: Molecular Cancer Research, Vol. 13, No. 11, 01.11.2015, p. 1478-1486.

Research output: Contribution to journalArticle

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T1 - Loss of stromal IMP1 promotes a tumorigenic microenvironment in the colon

AU - Hamilton, Kathryn E.

AU - Chatterji, Priya

AU - Lundsmith, Emma T.

AU - Andres, Sarah F.

AU - Giroux, Veronique

AU - Hicks, Philip D.

AU - Noubissi, Felicite K.

AU - Spiegelman, Vladimir

AU - Rustgi, Anil K.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - The colon tumor microenvironment is becoming increasingly recognized as a complex but central player in the development of many cancers. Previously, we identified an oncogenic role for the mRNA-binding protein IMP1 (IGF2BP1) in the epithelium during colon tumorigenesis. In the current study, we reveal the contribution of stromal IMP1 in the context of colitis-associated colon tumorigenesis. Interestingly, stromal deletion of Imp1 (Dermo1Cre;Imp1LoxP/LoxP, or Imp1δMes) in the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated cancer resulted in increased tumor numbers of larger size and more advanced histologic grade than controls. In addition, Imp1 δMes mice exhibited a global increase in protumorigenic microenvironment factors, including enhanced inflammation and stromal components. Evaluation of purified mesenchyme from AOM/DSS-treated Imp1δMes mice demonstrated an increase in hepatocyte growth factor (HGF), which has not been associated with regulation via IMP1. Genetic knockdown of Imp1 in human primary fibroblasts confirmed an increase in HGF with Imp1 loss, demonstrating a specific, cell-autonomous role for Imp1 loss to increase HGF expression. Taken together, these data demonstrate a novel tumor-suppressive role for IMP1 in colon stromal cells and underscore an exquisite, context-specific function for mRNA-binding proteins, such as IMP1, in disease states. Implications: The tumor-suppressive role of stromal IMP1 and its ability to modulate protumorigenic factors suggest that IMP1 status is important for the initiation and growth of epithelial tumors.

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Hamilton KE, Chatterji P, Lundsmith ET, Andres SF, Giroux V, Hicks PD et al. Loss of stromal IMP1 promotes a tumorigenic microenvironment in the colon. Molecular Cancer Research. 2015 Nov 1;13(11):1478-1486. https://doi.org/10.1158/1541-7786.MCR-15-0224