Tumorigenesis is associated with heterogeneous evolving changes of innate and adaptive immune effectors in the tumor microenvironment. Recording, identifying and quantifying these cellular and molecular changes could transform our understanding of tumorigenesis. We and others have shown that oncogenes, such as MYC co-opt and/or subvert these immune effectors, thereby evading immune detection and promoting a tumor microenvironment that fuels tumor growth; however, this appears to occur in a manner that necessarily and predictably leaves tumors highly vulnerable to acute oncogene inactivation, whereby immune effectors become activated, thereby resulting in dramatic tumor regression, a phenomenon called ?oncogene addiction?. Hence, we hypothesize that the identification?quantification and localization of these different host immune effectors in the tumor microenvironment during tumorigenesis and tumor regression will identify cellular biomarkers that will predict therapeutic response to oncogene inactivation. Our approach will be to employ the Tet system regulated model of MYC-induced hepatocellular carcinoma (HCC) and MYC/Twist1-induced model of metastatic HCC. Then, to utilize: FACS/CyTOF, CODEX/MIBI, IVM/BLI, and Gene expression/CIBERSORT to identify cellular effectors and hallmark genes and metabolites. First, our transgenic mouse model of MYC- induced HCC has been widely utilized by us and many others. Employing the Tet System, our model exhibit precise reversible and titrable control of the gene expression of the MYC oncogene. Tumor formation occurs slowly over time, oncogene-dependency results in tumor regression that is highly dependent on the immune response. Further, recently we generated a not published mouse model dramatically illustrating that MYC- induced liver tumors rapidly metastasize through the blood stream when combined with transgenic Twist1 expression. Twist1 has previously been associated with metastasis. We have obtained preliminary results that show metastasis is associated with and appears to require recruitment of macrophages. Finally, we have found that we can use human TCGA data available to identify potential cellular effectors associated with the pathogenesis of human HCC. Thus, all stages of tumorigenesis appear to be dependent on the stromal and immune response (initial, progressed, metastatic, regressed) and represent a unique tool to assess tumor- microenvironment heterogeneity. We have three aims: first, to dissect the mechanism by which the adaptive and innate immune system facilitates HCC progression, metastasis, and regression; second, to determine the kinetics and localizations of the above identified cell populations using in vivo (IVM and BLI) imaging technologies with special emphasis on cell-cell interactions and, third, to assess the ability of these findings to make predictions regarding the clinical behavior and prognosis of human HCC.
Previously, we have shown that the inactivation of MYC and other oncogene is sufficient to induce the sustained regression of cancer and phenomenon we call Oncogene Addiction. We have found that how MYC and other oncogenes initiate tumorigenesis and how their inactivation induces tumor regression is intimately connected with a immune response. Now, we propose to develop multiple novel methods to interrogate in situ the changes in the tumor microenvironment that mediate tumor initiation, progression and maintenance.
| Casey, Stephanie C; Baylot, Virginie; Felsher, Dean W (2018) The MYC oncogene is a global regulator of the immune response. Blood 131:2007-2015 |
| Dhanasekaran, Renumathy; Gabay-Ryan, Meital; Baylot, Virginie et al. (2018) Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC). Oncotarget 9:5517-5528 |
| Casey, Stephanie C; Baylot, Virginie; Felsher, Dean W (2017) MYC: Master Regulator of Immune Privilege. Trends Immunol 38:298-305 |
