Loss of Stromal IMP1 Promotes a Tumorigenic Microenvironment in the Colon

Abstract

The colon tumor microenvironment (TME) 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 histological grade than controls. In addition, Imp1ΔMes mice exhibited a global increase in pro-tumorigenic 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.

Comprehensive site-specific whole genome profiling of stromal and epithelial colonic gene signatures in human sigmoid colon and rectal tissue

“…These data provide insight into the gene expression landscape of the normal epithelium and stroma prior to the onset of intestinal tumorigenesis. This is noteworthy because the development of cancer is intimately linked to cross talk between cancer cells and the surrounding stromal cells (microenvironment) (19,43,55).…”

“…The development of colon cancer is intimately regulated by cross talk between the complex milieu of the stroma, containing fibroblasts, inflammatory immune cells and vascular cells, and the intestinal stem cell niche (19,28,43,55). Thus, colonic biopsies represent intestinal-specific transcriptional patterns consisting of signals originating from stromal and epithelial cells (7,12,24).…”

IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer

“…Loss of IMP1 in stromal cells did not appear to affect intestinal homeostasis or the constitution of the intestinal stroma itself. However, mice lacking IMP1 in their stromal cells developed a greater number of as well as larger tumors in response to AOM/DSS than their wild-type counterparts (Hamilton et al 2015). The inflammation provoked by AOM/DSS was more severe in mice lacking IMP1 in their stromal cells, and inflammatory cell infiltrates in the tumors were denser with stronger evidence of a wound healing-type response.…”

“…Thus, loss of IMP1 expression in the stroma has been reported recently to promote tumor growth in the azoxymethan (AOM)/dextran sodium sulphate (DSS) model of colitis-associated cancer (Hamilton et al 2015). IMP1-floxed mice were crossed with DermoCre animals, resulting in IMP1 deletion in mesoderm-derived tissues, including fibroblasts, macrophages, and endothelial cells as of E9.5.…”

IMPlicating Mesenchymal Imp1 in Colitis-Associated Cancer

“…However, colitis-induced tumorigenesis in these mice was markedly enhanced, with increased tumor numbers, tumor size, and incidence of adenocarcinomas (3). These data showing that protumorigenic effects following loss of Imp1 expression in fibroblasts were well correlated with increased inflammation, neutrophilia, stromal involvement, and fibrosis in the tissues of Dermo-Imp1 mice at the late stages of AOM/DSS model led the authors to hypothesize that Imp1 in the mesenchymal compartment is required to quickly and efficiently heal the tissue during chronic inflammation.…”