Director, Koch Institute for Integrative Cancer Research
David H. Koch Professor of Biology
Daniel K. Ludwig Scholar
Investigator, Howard Hughes Medical Institute
Ph.D. 1988, University of California, San Francisco
"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.
Dr. Jacks 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. His laboratory has made seminal contributions to the understanding of the effects of mutations of several common cancer-associated genes. This research has led to novel insights into tumor development, normal development and other cellular processes, as well as new strategies for cancer detection and treatment.
Dr. Jacks has published more than 200 scientific papers. He has served on the Board of Scientific Advisors of the National Cancer Institute (NCI) and the Board of Directors of the American Association of Cancer Research (AACR); he is also a past President of the AACR. He also serves as an advisor to several biotechnology and pharmaceutical companies. Dr. Jacks was a Merck Fellow of the Helen Hay Whitney Foundation, a Markey and a Searle Scholar and is currently a Daniel K. Ludwig Scholar in Cancer Research.
In recognition of his contributions to the study of cancer genetics, he received the AACR Outstanding Achievement Award and the Amgen Award from the American Society of Biochemistry and Molecular Biology, the Chestnut Hill Award for Excellence in Medical Research, the Paul Marks Prize for Cancer Research, and was named a member of MGH Cancer Center’s 2013 one hundred. He was elected to both the National Academy of Sciences and the Institute of Medicine of the National Academies in 2009, as well as the American Academy of Arts and Sciences in 2012 and the inaugural class of Fellows of the AACR Academy in 2013. He is also chair of the National Cancer Advisory Board.
Over the past several years, we have been studying cancer and cancer-related processes with a focus on in vivo approaches. Using increasingly precise methods of genetic engineering in the mouse, our laboratory has generated a series of novel strains containing germline mutations in several genes implicated in human cancer. Using these strains (as well as some from others), we have directed single or combinations of mutations to tissues and cells of interest, successfully developing a number of powerful new models of human cancer. These models resemble the human disease both at the genetic and phenotypic levels.
The development of tumor cells from normal cells requires the sequential acquisition of mutations in several cellular genes. In general, two classes of genes are affected in tumor progression: genes that normally act to promote cell division (oncogenes) and genes that function to arrest or inhibit cell division (tumor-suppressor genes). Human familial cancer syndromes (in which affected individuals have a greatly increased risk of developing particular types of cancer) are often caused by the inheritance of a mutant allele of a tumor suppressor gene or an activated allele of an oncogene. Tumor suppressors are thought to regulate cell growth negatively, and they contribute to carcinogenesis when mutated or lost. Thus, individuals who carry only one functional copy of a given tumor suppressor gene are predisposed to cancer, because all of their cells are just one mutational event from lacking an important negative growth regulator.
Many tumors of epithelial origin in humans acquire mutations in the K-ras oncogene, including approximately 30% of non-small cell lung cancer (NSCLC), 50% of colon cancers, and 90% of pancreatic cancers. Our laboratory has been investigating the effects of K-ras mutation in the mouse. In order to control timing and tissue-specific activation of K-ras, we have developed a conditional, activatable allele of the K-ras oncogene, and have used it to generate various mouse models of human cancer. In the lung, activation of oncogenic K-ras leads to the development of atypical adenomatous hyperplasia, adenomas, and adenocarcinomas. Combining mutations in K-ras and p53 in the lung led to the development of more advanced tumors, which exhibited desmoplastic stroma, increased invasiveness and metastatic potential.
Using advanced gene targeting methods, generating mouse models of cancer that accurately reproduce the genetic alterations present in human tumors is now relatively straightforward. The challenge is to determine to what extent such models faithfully mimic human disease with respect to the underlying molecular mechanisms that accompany tumor progression. Working with the Golub lab at the Broad Institute, we have developed a method for comparing mouse models of cancer with human tumors using gene expression profiling. We applied this method to the analysis of our model of Kras-mediated lung cancer and found a good relationship to human lung adenocarcinoma, thereby validating the model. Furthermore, we found that whereas a gene-expression signature of KRAS activation was not identifiable when analyzing human tumors with known KRAS mutation status alone, integrating mouse and human data uncovered a gene-expression signature of KRAS mutation in human lung cancer. The K-ras lung cancer model has also been used in collaboration with the Golub laboratory to perform miRNA profiling experiments. The data from the model are consistent with human data, demonstrating a general down regulation of miRNA expression in tumors compared to normal tissue.
Through analysis of the expression profiling data, we identified cathepsin cysteine proteases as being highly up-regulated in lung cancer specimens. In collaboration with the Weissleder group at MGH, we demonstrated that an optical probe activated by cathepsin proteases could detect murine lung tumors in vivo as small as 1 mm in diameter. By serially imaging the same mouse, optical imaging was used to follow tumor progression. This cathepsin-imaging strategy is now being evaluated for use in intra-operative imaging during surgical resection of mouse tumors, with the hope that it could improve local control of cancer in humans.
Injury models have suggested that the lung contains anatomically and functionally distinct epithelial stem cell populations. We have isolated such a regional pulmonary stem cell population, termed bronchioalveolar stem cells (BASCs). These stem cells were enriched, propagated, and differentiated in vitro and found to be activated by the oncogenic protein K-ras. Our studies suggest that BASCs are a stem cell population that maintains the bronchiolar Clara cells and alveolar cells of the distal lung and that their transformed counterparts give rise to adenocarcinoma.
For several years, we have been attempting to develop mouse models of familiar retinoblastoma (caused by a germline mutation in the RB gene) and of Li-Fraumeni syndrome (LFS; caused by a germline p53 tumor-suppressor gene mutation). While mice heterozygous for null mutations in Rb or p53 are cancer prone, they do not exhibit the spectrum of tumors observed in the relevant human syndromes. Using more sophisticated methods in gene targeting technology as well as compound mutant analysis, we have now created strains that do develop retinoblastoma and the tumor types seen in LFS. Rb mutation in the retina does not result in retinoblastoma formation even in the absence of p53. However, on either a p107- or p130-deficient background, Rb mutation in the retina causes retinal dysplasia and retinoblastoma. This represents the first breedable model of retinoblastoma. We have recently performed DNA copy number analysis on these retinoblastomas and observed genomic amplification of the N-myc oncogene. N-myc amplification also occurs in a subset of human retinoblastomas. Finally, we have also studied the role of pRb, p107, and p130 in the regulation of cell cycle progression and terminal differentiation in various tissues of the mouse.
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.
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.