Mouse models of intestinal cancer have been instrumental in understanding oncogenesis and most recently have shed light on the role of innate immunity and the commensal microbiota in colon cancer. Under the aegis of this grant, we recently described a new model of commensal-dependent ulcerative colitis termed T-bet-/- RAG2-/- Ulcerative Colitis (TRUC) that results from T-bet deficiency in the innate immune system. T-bet is a T- box family transcription factor that controls chemokine and cytokine production, regulates host-commensal homeostasis in the colon, and is expressed only in immune cells. Increased levels of T-bet in human colorectal tumors correlate with increased patient survival. TRUC mice develop a severe and highly penetrant colitis driven in part by loss of TNF? regulation in the colon that can be reversed by antibiotics, TNF? blockers, transfer of T regulatory cells or dendritic cell depletion. We have discovered that the majority of TRUC mice spontaneously progress to colonic dysplasia and colorectal adenocarcinoma (CRC) that is dependent on intestinal inflammation. TRUC-associated CRC resembles the human disease, and as a novel pre-clinical model, provides ample opportunity to probe how the inflammatory milieu drives the development of CRC and to test preventative and therapeutic strategies. More work needs to be done, however, to establish the similarity of TRUC colitis associated CRC to the human disease. TRUC colitis and CRC are, in contrast to most other mouse colitis models, independent of Myd88 signaling giving us the opportunity to identify non- Myd88 driven pathways and mediators that may intersect with known Myd88 instigated pathways. Despite a complex inflammatory environment rich in cytokines, growth factors, proteases, inflammatory mediators and significant DNA damage, restoration of T-bet selectively in dendritic cells (DCs) was sufficient to reduce colonic inflammation and prevent the development of neoplasia. The mechanism by which T-bet is activated in DCs to initiate colitis, however, and the generalizability of T-bet function in DCs to other models of inflammatory colitis and CRC is unknown. The overarching theme of this proposal is to understand how T-bet and TRUC associated genetic modifier genes control the development of inflammation associated cancer and to harness that function therapeutically. We propose to 1. Explore the similarity of TRUC caCRC to the human disease and test its therapeutic response to cytokine blockade at various stages of dysplasia;2. Explore how T-bet in dendritic cells controls inflammation driven CRC.;and 3. Identify genetic modifier genes associated with TRUC.
We recently described a new model of commensal-dependent ulcerative colitis (TRUC) that results from deficiency of the transcription factor T-bet in the innate immune system, and have now discovered that the majority of TRUC mice spontaneously progress to colonic dysplasia and rectal adenocarcinoma that is dependent on intestinal inflammation. TRUC-associated colorectal cancer resembles the human disease, and as a novel pre-clinical model, provides ample opportunity to probe how the inflammatory milieu drives the development of colorectal cancer and to test preventative and therapeutic strategies.
|Cubillos-Ruiz, Juan R; Bettigole, Sarah E; Glimcher, Laurie H (2017) Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer. Cell 168:692-706|
|Cubillos-Ruiz, Juan R; Bettigole, Sarah E; Glimcher, Laurie H (2016) Molecular Pathways: Immunosuppressive Roles of IRE1?-XBP1 Signaling in Dendritic Cells of the Tumor Microenvironment. Clin Cancer Res 22:2121-6|
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|Ermann, Joerg; Staton, Tracy; Glickman, Jonathan N et al. (2014) Nod/Ripk2 signaling in dendritic cells activates IL-17A-secreting innate lymphoid cells and drives colitis in T-bet-/-.Rag2-/- (TRUC) mice. Proc Natl Acad Sci U S A 111:E2559-66|
|Lazarevic, Vanja; Glimcher, Laurie H; Lord, Graham M (2013) T-bet: a bridge between innate and adaptive immunity. Nat Rev Immunol 13:777-89|
|Ermann, Joerg; Glimcher, Laurie H (2012) After GWAS: mice to the rescue? Curr Opin Immunol 24:564-70|
|Ermann, Joerg; Garrett, Wendy S; Kuchroo, Juhi et al. (2011) Severity of innate immune-mediated colitis is controlled by the cytokine deficiency-induced colitis susceptibility-1 (Cdcs1) locus. Proc Natl Acad Sci U S A 108:7137-41|
|Lazarevic, Vanja; Glimcher, Laurie H (2011) T-bet in disease. Nat Immunol 12:597-606|
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