Colon cancer is the third most common cancer and the third leading cause of cancer-related mortality in the United States. For many years it was believed that colorectal cancers (CRC) evolved from advanced adenomatous polyps. In recent years, however, convincing evidence has emerged that a significant proportion of CRC develops within a small subset of serrated polyps, through a mechanism that is different from those responsible for the adenoma-carcinoma developmental progression. The two most common epithelial polyp in the colorectum are adenomas and serrated polyps. Serrated polyps are morphologically characterized by a saw-toothed unfolding of the crypt epithelium. Currently, serrated polyps are grouped in 4 major categories: hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed serrated polyps. Serrated polyps have a striking subtype dependent location in the gut. Hyperplastic polyps are most frequently found in the left colon and rectum, while sessile serrated adenomas are usually found in the right colon. Historically, hyperplastic polyps have been considered to have little or no malignant potential. This view, however, has changed recently, as evidence has emerged that hyperplastic polyps display molecular features seen in neoplastic lesions, such as microsatellite instability (MSI), aberrant DNA methylation, and mutations in BRAF and KRAS genes. In addition to KRAS and BRAF mutations, our work suggests that activation of the EGFR receptor also promotes the development of serrated polyps. We have developed a novel model for serrated polyps in mice that represents a subset of human serrated polyps that arise independent of activating mutations in BRAF or KRAS, but rather occur due to increased activity of the EGFR receptor. This model presents morphological and biochemical similarities to serrated polyps in humans. Strikingly, similar to human serrated polyps, serrated polyps in HBUS mice develop in a specific location of the gut and are dependent on both genetic and environmental factors. In this proposal we will investigate how one such an environmental factor, namely the microbiota, affects the development of serrated polyps.
Aim 1 is focused on the identification of the causative organism(s).
Aim 2 is aimed at understanding how the microbiota affects the host and how this leads to the development of serrated polyps. A team of experts in microbiome (J. Faith, and J.C. Clemente, Sinai), microRNA biology (B. Brown, Sinai), methylome (Daniel Carvalho, Toronto) and pathology (Noam Harpaz, Sinai) will assist us in these studies.
Colon cancer is the third most common cancer and the third leading cause of cancer-related mortality in the United States. A proportion of colorectal cancer develops within a subset of lesions called serrated lesions. We have generated genetically modified mice that develop such lesions and showed that the complex communities of non-pathogenic commensal bacteria play a role in the development of intestinal lesions. The study of this novel cancer model may contribute to a better understanding of the mechanisms leading to the formation of serrated lesions and to the development of new strategies for its prevention and treatment.
| Meisel, Marlies; Hinterleitner, Reinhard; Pacis, Alain et al. (2018) Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 557:580-584 |
| Dong, Xiaonan; Cheng, Adam; Zou, Zhongju et al. (2016) Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis. Proc Natl Acad Sci U S A 113:2994-9 |
| Parkunan, Salai Madhumathi; Randall, C Blake; Astley, Roger A et al. (2016) CXCL1, but not IL-6, significantly impacts intraocular inflammation during infection. J Leukoc Biol 100:1125-1134 |
| Cummings, Ryan J; Barbet, Gaetan; Bongers, Gerold et al. (2016) Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs. Nature 539:565-569 |
| Lu, Geming; Zhang, Ruihua; Geng, Shuo et al. (2015) Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Nat Commun 6:6676 |
| Brix, Silke R; Stege, Gesa; Disteldorf, Erik et al. (2015) CC Chemokine Ligand 18 in ANCA-Associated Crescentic GN. J Am Soc Nephrol 26:2105-17 |
| Chen, Lili; He, Zhengxiang; Slinger, Erik et al. (2015) IL-23 activates innate lymphoid cells to promote neonatal intestinal pathology. Mucosal Immunol 8:390-402 |
| Disteldorf, Erik M; Krebs, Christian F; Paust, Hans-Joachim et al. (2015) CXCL5 drives neutrophil recruitment in TH17-mediated GN. J Am Soc Nephrol 26:55-66 |
| Berres, Marie-Luise; Lim, Karen Phaik Har; Peters, Tricia et al. (2014) BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 211:669-83 |
| Noriega, Vanessa M; Gardner, Thomas J; Redmann, Veronika et al. (2014) Human cytomegalovirus US28 facilitates cell-to-cell viral dissemination. Viruses 6:1202-18 |
Showing the most recent 10 out of 17 publications
