The Jacks Lab @Koch Institute for Integrative Cancer Research at MIT
Reporter: Aviva Lev-Ari, PhD, RN
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SOLUTIONS with/in/sight: Masterclass with Tyler Jacks
Wednesday, May 25, 2016; 6:00 p.m. – 8:30 p.m.
Can your own immune system effectively fight cancer in the same way that it fights against viruses and bacteria? Indeed, cancer immunotherapy was declared the Breakthrough of the Year by Science Magazine in 2013, and these new treatments are having a major impact for several types of cancer. Join Koch Institute director Tyler Jacks as he presents new discoveries and promising technologies in the field of cancer immunology and immunotherapy. He will share research from his own laboratory about the immune system’s response to cancer, and highlight MIT’s collaborative, interdisciplinary approach to re-engineering immune cells to destroy tumors.
“The Jacks Lab has pioneered the use of gene-targeting technology in the mouse to study cancer-associated genes and to construct mouse models of many human cancer types, including cancers of the lung, brain, and ovary.”
Tyler Jacks is the director of the Koch Institute for Integrative Cancer Research at MIT. Dr. Jacks received his B.A. in Biology from Harvard College in 1983. His Ph.D. thesis was performed with Harold Varmus at the University of California, San Francisco. He was a post-doctoral fellow with Robert Weinberg at the Whitehead Institute at MIT. He joined the faculty at MIT in 1992.
SOURCE
https://ki.mit.edu/people/faculty/jacks
The majority of human tumors have mutations in the p53 gene. The development of a more accurate model of LFS required the construction of knock-in strains carrying missense mutations of p53 (as opposed to the original null mutations). These p53 point mutants are thought to act as dominant-negative proteins and have been proposed to have dominant gain-of-function effects as well. We demonstrated that mice heterozygous for either of two p53 point mutations developed a broader spectrum of tumors than mice heterozygous for a p53 null allele. This included the development of carcinomas, which are frequent in LFS and rare in the p53+/- mouse. By comparing tumor phenotype in p53R172H/- or p53R270H/- mice with p53-/- mice, we also addressed possible gain-of-function effects. Indeed, the point mutant alleles promoted the development of carcinomas, which do not occur in p53-/- mice. Thus, we provided the first support in vivo for a gain-of-function of tumor-associated point mutations in p53.
We have also been studying whether the reactivation of p53 could have therapeutic effect in established tumors using a Cre-Lox based approach. We have observed dramatic response to p53 restoration in nearly all tumors tested to date. Interestingly, the response to the reactivation of p53 differed between tumor types, with lymphomas undergoing apoptosis and sarcomas undergoing cell cycle arrest with features of senescence. This work indicates that the signaling pathways that impinge on p53 remain active in established tumors and provides support for efforts to activate this pathway in human cancer therapy.
Finally, we have continued to develop additional mouse tumor models, including several representing major human cancer types for which good pre-clinical models have been lacking. These include pancreatic cancer, ovarian cancer, soft tissue sarcoma, and invasive colon cancer.
Selected Publications
Joshi NS, Jacks T. 2013. Immunology. Guilty by association. Science. 8;339(6124):1160-1.
DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T. 2012. Expression of tumour-specific antigens underlies cancer immunoediting. Nature, 482(7385):405-409. PDF
Xue W, Meylan E, Oliver TG, Feldser DM, Winslow MM, Bronson R, Jacks T. 2011. Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma. Cancer Discovery, 1(3):236-47. PMCID: PMC3160630
DuPage M, Cheung A, Mazumdar , Winslow MM, Bronson R, Schmidt LM, Crowley D, Chen J, and Jacks T. 2011. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer Cell, 19(1):72-85. PMCID: PMC3069809.
Feldser DM, Kostova KK, Winslow MM, Taylor SE, Cashman C, Whittaker CA, Sanchez-Rivera FJ, Resnick R, Bronson R, Hemann MT, and Jacks T. 2010. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature, 468 (7323):572-575. PMCID: PMC3003305.
Meylan E, Dooley AL, Feldser DM, Shen L, Turk E, Ouyang C, Jacks T. 2009. Requirement for NF-kB signaling in a mouse model of lung adenocarcinoma. Nature, 462(7269):104-107. PMCID: PMC2780341
Ventura, A., Young, A., Winslow, M., Lintault, L., Meissner, A., Erkeland, S., Newman, J., Bronson, R., Crowley, D., Stone, J., Jaenisch, R., Sharp, P., Jacks T. 2008. Targeted deletion reveals essential and overlapping functions of the miR-17~92 family of miRNA clusters. Cell, 132, 875-886. PMCID:PMC2323338
Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R and Jacks T. 2007. Restoration of p53 function leads to tumor regression in vivo. Nature 445, 661-665
Jackson EL, Willis N, Mercer K, Bronson RT, Crowley D, Montoya R, Jacks T, Tuveson DA. 2001. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15(24):3243-8.
Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, Jacks T. 2001. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature. 410(6832):1111-6.
Search PubMed for Jacks Lab publications
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