Abstract 931: HMGA1 drives expansion of the intestinal stem cell compartment in transgenic mice and tumor progression in colon cancer cells

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The molecular mechanisms that enable colon cancer cells to evade therapy and metastasize are poorly understood and have not been effectively targeted by current therapies. Recent evidence suggests that tumor cells with stem-like properties (poor differentiation, long-term self-renewal, and a relatively quiescent state) are responsible for metastatic progression and resistance to therapy. Our laboratory is investigating molecular pathways that give rise to metastatic progression and “stemness” in refractory colon cancer with the long-term goal of identifying novel therapeutic targets. Our focus is the HMGA1 gene, which encodes the HMGA1a and HMGA1b chromatin remodeling proteins. HMGA1 is highly expressed during embryogenesis, but not in differentiated, adult tissues. Strikingly, HMGA1 is overexpressed in virtually all high-grade (poorly differentiated) cancers studied to date. To study the role of HMGA1 in tumor progression and the stem cell state, we engineered HMGA1a transgenic mice. As previously reported, these mice succumb to aggressive lymphoid malignancies. Here, we report that the HMGA1 transgenics also develop hyperproliferative changes in the intestines with hamartomatous polyps. In addition, we found that the HMGA1 mice develop an expansion in the intestinal stem cell compartment, suggesting that HMGA1 promotes the maintenance or survival of intestinal stem cells. To assess the role of HMGA1 in tumor progression and the stem cell phenotype in colon cancer, we inhibited HMGA1 expression in the poorly differentiated, HCT116 colon cancer cell line. We found that knock-down of HMGA1 blocks anchorage-independent cell growth, migration, and invasion in vitro. We also demonstrate that knock-down of HMGA1 blocks tumorigenesis and metastatic progression in vivo. Moreover, three-dimensional colonosphere formation is decreased in the knock-down cells, indicating that HMGA1 is required for this stem cell phenotype. To further assess the role of HMGA1 in colon cancer stem cells, we performed limiting dilution tumorigenesis experiments. Inhibiting HMGA1 expression blocks tumorigenesis at limiting dilutions, consistent with depletion of tumor-initiator cells in the HMGA1 knock-down cells. In HCT116 cells, we also found that HMGA1 induces expression of Vimentin and Twist1, two genes involved in embryogenesis, EMT, and tumor progression. Analysis of prior gene expression profile analyses show that HMGA1 is among the most enriched genes in colon cancer compared to normal mucosa and we confirmed this by quantitative, RT-PCR in a subset of primary, high-grade tumors. Taken together, these findings suggest that HMGA1 drives tumor progression by inducing a stem-like state. Although further studies are needed, our results also suggest that HMGA1 or downstream pathways could be rational therapeutic targets in poorly differentiated colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 931. doi:10.1158/1538-7445.AM2011-931