Hmga1 Amplifies Wnt Signaling And Expands The Intestinal Stem Cell Compartment To Drive Premalignant Polyposis In Transgenic Mice

Emerging evidence suggests that cancer cells undergo chromatin remodeling and epigenetic reprogramming to co-opt stem cell properties and drive tumor progression. The HMGA1 chromatin remodeling protein is an architectural transcription factor that binds to DNA at AT-rich sequences where it “opens” chromatin, recruits transcriptional complexes, and modulates gene expression. The HMGA1 gene is highly expressed during embryogenesis and in adult stem cells, but silenced postnatally in differentiated tissues. HMGA1 becomes re-expressed in most high-grade cancers and high levels portend adverse clinical outcomes. In colon cancer, HMGA1 is among the genes most highly overexpressed compared to normal intestinal epithelium. We previously reported that HMGA1 drives tumor progression in colon cancer by inducing stem cell genes involved in an epithelial-mesenchymal transition. We also discovered that Hmga1 transgenic mice develop marked proliferative changes and pre-malignant polyposis in the intestinal epithelium. To determine how Hmga1 functions in the intestines during tissue homeostasis and carcinogenesis, we examined in transgenic mice and organoid models. Here, we uncover a novel role for Hmga1 in maintaining the intestinal stem cell (ISC) pool and Paneth cell niche. Hmga1 is required by ISCs to organize into three-dimensional organoids in vitro; silencing Hmga1 disrupts organoid formation and bud development. Conversely, overexpression of Hmga1 increases organoid formation, bud development, and replating efficiency, suggesting that Hmga1 enhances ISC function and/or number. We therefore crossed the Hmga1 transgenic mice onto the Lgr5-EGFP background to enumerate ISCs and found that Hmga1 expands the ISC compartment. To determine how this occurs, we performed in vivo imaging and discovered that Hmga1 enhances self-renewal of ISCs. Mechanistically, we found that Hmga1 amplifies Wnt/β-catenin signaling by inducing genes encoding both Wnt agonist receptors and downstream Wnt target genes. Surprisingly, Hmga1 also expands the Paneth cell niche, which is comprised of terminally differentiated crypt cells that secrete Wnt to support ISCs. Because Paneth cells require Sox9 for development, we determined whether Hmga1 regulates its expression. Hmga1 binds directly to the Sox9 promoter at 2 AT-rich sites to activate its expression. In human colonic epithelium, HMGA1 and SOX9 are positively correlated, and both become markedly up-regulated in colon carcinogenesis. This work not only provides new insights into the role of Hmga1 in intestinal homeostasis by maintaining both the stem cell pool and epithelial niche compartment, but also suggests that deregulated Hmga1 perturbs this equilibrium during polyposis and carcinogenesis. Our results also highlight the HMGA1-WNT-SOX9 pathway as rational therapeutic target in colon carcinogenesis. Citation Format: Lingling Xian, Dan Georgess, Li Luo, Lionel Chia, Qihua Gu, Tait Huso, Amy Belton, David Huso, Andrew Ewald, Linda M.S. Resar. HMGA1 amplifies Wnt signaling and expands the intestinal stem cell compartment to drive premalignant polyposis in transgenic mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5019. doi:10.1158/1538-7445.AM2017-5019