Using Genetically Engineered Mouse Models (GEMMs) to Study Sarcoma and Radiation Biology
GEMMs allow tumors to develop in their native microenvironment in animals with intact immune systems that more closely resemble the natural history of human tumors. These advantages over traditional xenografts make GEMMs ideal preclinical platforms to study tumor biology and test new therapies. We have generated a spatially and temporally restricted mouse model of soft tissue sarcoma. We have utilized this model to perform cross species genomic analysis to demonstrate that the mouse model is similar to human sarcoma. This model has also been useful for developing and testing new therapies. For example, working with engineers at MIT, we have developed an intraoperative imaging system to detect microscopic residual disease in the tumor bed of mice at the time of surgery, which is now in clinical trials. We continue to use this mouse model to study sarcoma biology including the mechanisms underlying tumor heterogeneity, metastasis, and response to conventional and targeted cancer therapies.
Kirsch DG*, Dinulescu DM*, Miller JB, Grimm J, Santiago PM, Young NP, Nielsen GP, Quade BJ, Chaber CJ, Schultz CP, Takeuchi O, Bronson RT, Crowley D, Korsmeyer SJ, Yoon SS, Hornicek FJ, Weissleder R, Jacks, T. A Spatially and Temporally Restricted Mouse Model of Soft Tissue Sarcoma. Nature Medicine 2007;13:992-997.*=equal contribution. PMID: 17676052
Mito JK, Ferrer JM, Brigman BE, Lee CL, Dodd RD, Eward WC, Marshall LF, Cuneo KC, Carter JE, Ramasunder S, Kim Y, Lee WD, Griffith LG, Bawendi MG, Kirsch DG. Intraoperative detection and removal of microscopic residual sarcoma using wide-field imaging. Cancer. 2012 Nov 1; 118(21): 5320-30.PMCID:PMC3532657
Sachdeva M, Mito JK, Lee CL, Zhang M, Li Z, Dodd R, Cason D, Luo L, Ma Y, VanMater D, Gladdy R, Lev DG, Cardona DM, Kirsch DG. MicroRNA-182 Drives Metastasis of Primary Sarcomas by Targeting Multiple Genes. Journal of Clinical Investigation. 2014 In Press.
Genetically Engineered Mouse Models (GEMMs) of Cancer to Study Radiation Therapy
We are using primary mouse models of non-small cell lung cancer and soft tissue sarcomas to investigate mechanisms of tumor response to radiation therapy. Utilizing state-of-the-art small animal imaging and irradiation, we can monitor tumor growth and deliver targeted radiation therapy to cancer in mice. By combining novel mouse models of cancer and cutting edge imaging tools, we are investigating the mechanisms that mediate tumor eradication after radiation therapy.
Kirsch DG, Grimm J, Guimaraes AR, Wojtkiewicz G, Perez BA, Santiago PM, Anthony NK, Forbes T, Doppke K, Weissleder R, Jacks T. Imaging Primary Lung Cancers in Mice to Study Radiation Biology. International Journal of Radiation Oncology, Biology, Physics. 2010 March 15; 76(4):973-977. PMCID: PMC2847457
Yoon SS, Stangenberg L, Lee YJ, Rothrock C, Dreyfuss JM, Baek KH, Waterman PR, Nielsen GP, Weissleder R, Mahmood U, Park PJ, Jacks T, Dodd RD, Fisher CJ, Ryeom S, Kirsch DG. Efficacy of sunitinib and radiotherapy in genetically engineered mouse model of soft-tissue sarcoma. Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):1207-16. Erratum in: Int J Radiat Oncol Biol Phys. 2010 Aug 1;77(5):1607. PMCID: PMC2733223
Generating Novel Genetically Engineered Mice to Study Cancer: Dual Recombinase Technology
We are constantly generating new tools to better recapitulate human cancer using mouse models. We have developed p53FRT mice to enable dual recombinase technology to selectively mutate different genes contemporaneously in tumor parenchymal cells and stomal cells. We are using this technology to investigate the contribution of the microenvironment to tumor development, progression, and response to therapy. We have recently applied dual recombinase technology to initiate primary sarcomas in mice and delete genes specifically in endothelial cells to define the contribution of endothelial cell death to tumor response to radiation therapy.
Lee CL, Moding EJ, Huang X, Li Y, Woodlief LZ, Rodrigues RC, Ma Y, Kirsch DG. Generation of primary tumors with Flp recombinase in FRT-flanked p53 mice. Disease, Models, and Mechanisms. 2012 May;5(3):397-402. PMCID: PMC3339833
Moding EJ, Lee CL, Castle KD, Oh P, Zha S, Min HD, Ma Y, Das S, Kirsch DG. ATM Deletion with Dual Recombinase Technology Preferentially Radiosensitizes Tumor Endothelium. Journal of Clinical Investigation. 2014 Aug 1;124(8):3325-38. PMCID:PMC4109553
Studying Normal Tissue Radiation Injury
To improve radiation therapy, it will be important to limit radiation toxicity to normal tissues. We are using GEMMs to investigate the mechanisms of normal tissue injury following radiation exposure to the heart, bone marrow, and intestines. In addition, we have received a grant from NASA to use mouse models to study radiation-induced lung cancer following exposure to space radiation.
Kirsch DG, Santiago PM, di Tomasso E, Sullivan JM, Hou W-S, Dayton T, Jeffords LB, Sodha P, Mercer K, Cohen R, Takeuchi O, Korsmeyer S, Bronson R, Kim CF, Haigis KM, Jain RK, Jacks T. p53 Controls Radiation-induced Gastrointestinal Syndrome in Mice Independent of Apoptosis. Science 2010;327:593-596. PMCID: PMC2897160
Lee CL, Moding EJ, Cuneo KC, Li Y, Sullivan JM, Mao L, Washington I, Jeffords LB, Rodrigues RC, Ma Y, Das S, Kontos CD, Kim Y, Rockman HA, Kirsch DG. p53 Functions in Endothelial Cells to Prevent Radiation-Induced Myocardial Injury in Mice. Science Signaling.2012 Jul 24; 5(234). PMCID:PMC3533440