Professor of Biology
Associate Director, Koch Institute for Integrative Cancer Research
Virginia & D.K. Ludwig Professor for Cancer Research
Director, MIT Stem Cell Initiative
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"Our research is focused on identifying the proteins and pathways that play a key role in tumorigenicity and establishing the mechanism of their action in both normal and tumor cells. We approach this using a combination of molecular and cellular analyses, mutant mouse models, and genetic screens in zebrafish. We have cloned a family of transcription factors, called E2F, that control the expression of genes that are essential for cellular proliferation. The activity of the E2Fs is regulated by their interaction with a second family of proteins called the pocket proteins, which includes the retinoblastoma protein, a tumor suppressor that is functionally inactivated in all human tumors. Our current goal is to understand how the interplay between the various E2F and pocket proteins mediates the appropriate control of cell cycle entry and exit that is required for normal development and tumor suppression."
Learn more about the work of the Lees laboratory to understand how proteins and pathways are mutated in cancer—and how they hope to make advances in detecting and treating osteosarcoma by watching this video: "Inside the Lab: Jacqueline A. Lees, Ph.D."
Dr. Lees is Associate Director at the Koch Institute and a professor of biology at MIT. She received her Ph.D. in 1990 from the University of London.
We have cloned a family of transcription factors, called E2F, that control the expression of genes that are essential for cellular proliferation. The activity of the E2Fs is regulated by their interaction with a second family of proteins called the pocket proteins. This includes the retinoblastoma protein (pRB), a tumor suppressor that is functionally inactivated in all human tumors, and two related proteins, p107 and p130. Pocket protein binding is sufficient to block the transcriptional activity of the E2Fs. Moreover, the resulting complexes can actively repress E2F-responsive genes by recruiting histone deactylases. Thus, the E2Fs have the potential to mediate either the repression or activation of E2F-responsive genes. Depending on the balance of these two activities, the E2F/pocket protein complexes control a mammalian cell's decision to proliferate or to exit the cell cycle. Significantly, the tumor-derived forms of pRB are all disrupted in their ability to interact with E2F. This strongly suggests that E2F plays a key role in the development of human tumors.
Our current goal is to understand how the interplay between the various E2F and pocket proteins mediates the appropriate control of cell cycle entry and exit that is required for normal development and tumor suppression. We are addressing this question using mutant mouse models and the resulting E2F/pocket protein deficient cells. These studies show that the E2F proteins can be divided into three distinct subgroups that have unique biological properties.
E2F1, 2, and 3 are potent transcriptional activators that are specifically regulated by pRB, and not p107 or p130, in vivo. We have shown that E2F3 plays a key role in activating almost all E2F-responsive genes and thereby determines the rate of proliferation of both normal and tumor cells. E2F3 is essential for full viability and E2f3 homozygous and heterozygous mutant mice display a variety of developmental abnormalities that are consistent with a dose-dependent requirement for E2F3 in the induction of proliferation. Importantly, through the generation and analysis of Rb:E2f compound mutant mice, we have shown that the tumor suppressive properties of pRB are primarily dependent upon its ability to inhibit the activating E2Fs, E2F1, 2, and 3. We are continuing to study how the interplay between pRB and the activating E2Fs controls both normal proliferation and tumorigenesis.
In contrast to the activating E2Fs, E2F4 and 5 lack nuclear localization signals and can only exist in the nucleus when bound to the pocket protein/histone deactylase complexes. Our analysis of compound E2f4:pocket protein mutant mice and cells indicates that the E2F4/pocket protein complexes play a key role in the repression of E2F-responsive genes. Consistent with this observation, these complexes are required for cells to exit the cell cycle in response to normal growth arrest signals and they are also essential for the terminal differentiation of a wide variety of cell lineages. Significantly, using in vitro differentiation assays, we have shown that E2F4 plays a key role in the differentiation process that is independent of any effect on cell cycle regulation. We are continuing to investigate the underlying basis for this activity.
E2F6 lacks the sequences necessary for either pocket protein binding or transcriptional activation and it participates in the repression of E2F-responsive genes through recruitment of a mammalian polycomb complex. At least one component of this polycomb complex, Bmi-1, has been shown to promote cell cycle progression and tumorigenesis. We continue to study the role of E2F6 and its associated polycomb complex in cell cycle control, normal development, and tumorigenicity.
As a collaborative effort with the Hopkins lab, we are using zebrafish to conduct large-scale screens for growth control and cancer genes. The Hopkins lab has generated a collection of several hundred zebrafish lines that contain heterozygous mutations within genes that are essential for embryonic development. Since the vast majority of known mammalian tumor suppressors are required for embryonic viability, we hypothesized that this collection might include novel tumor suppressor genes. To test this notion, we have monitored the heterozygote mutant strains for evidence of reduced lifespan and externally visible tumors. To date, this screen has led to the identification of eight different genes whose mutation renders the fish highly tumor-prone.
Importantly, one of these genes is a zebrafish paralogue of a known mammalian tumor suppressor gene, validating zebrafish as a powerful genetic tool in the search for cancer genes. The other seven genes have not previously been identified as tumor suppressors. We are now using both zebrafish and mouse models to understand how the encoded proteins inhibit tumor development. We are also continuing to screen the heterozygous mutant zebrafish for additional cancer-prone lines and have established a second screen to identify genes that are essential for cell cycle regulation.
Parisi T, Balsamo M, Gertler F, Lees JA. The Rb tumor suppressor regulators epithelial cell migration and polarity. Mol Carcinog. 2018 Nov;57(11):1640-1650. doi: 10.1002/mc.22886. Epub 2018 Aug 26.
Perez DE, Henle AM, Amsterdam A, Hagen HR, Lees JA. (2018). Uveal Melanoma driver mutation in GNAQ/11 yield changes in melanocyte biology. Pigment Cell Melanoma Res. 2018 Mar 23. doi: 10.1111/pcmr.12700. [Epub ahead of print]
Braun CJ, Stanciu M, Boutz PL, Patterson JC, Calligaris D, Higuchi F, Neupane R, Fenoglio S, Cahill DP, Wakimoto H, Agar NYR, Yaffe MB, Sharp PA, Hemann MT, Lees JA. Coordinated splicing of regulatory detained introns within oncogenic transcripts creates an exploitable vulnerability in malignant glioma. Cancer Cell. 2017 Oct 9;32(4):411-426.e11. doi: 10.1016/j.ccell.2017.08.018. Epub 2017 Sep 28.
Guen, V. J., Chavarria, T. E., Kröger, C., Ye, X., Weinberg, R. A., & Lees, J. A. (2017). EMT programs promote basal mammary stem cell and tumor-initiating cell stemness by inducing primary ciliogenesis and Hedgehog signaling. Proceedings of the National Academy of Sciences, 201711534.
Roper, J., Tammela, T., Cetinbas, N. M., Akkad, A., Roghanian, A., Rickelt, S., ... Lees, J…. Yilmaz, Omer. (2017). In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis. Nature biotechnology, 35(6), 569.
Guen, V. J., Gamble, C., Lees, J. A., & Colas, P. (2017). The awakening of the CDK10/Cyclin M protein kinase. Oncotarget, 8(30), 50174.
Ferretti R, Bhutkar A, McNamara MC, Lees JA. BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance. (2016) Genes and Development. 30(1):18-33 doi: 10.1101/gad.267757.115. Epub 2015 Dec 17 PMID: 26679841 PMCID: PMC4701976
Parisi T, Bronson RT, Lees JA. (2015) Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer. Oncogene. Nov 26;34(48):5890-9. doi: 10.1038/onc.2015.30. Epub 2015 Mar 9. PMCID: PMC4668801.
McFaline-Figueroa, J. L., Braun, C. J., Stanciu, M., Nagel, Z. D., Mazzucato, P., Sangaraju, D., ... Lees, J. A. …& Tretyakova, N. (2015). Minor changes in expression of the mismatch repair protein MSH2 exert a major impact on glioblastoma response to temozolomide. Cancer research.
Maynard MA, Ferretti R, Hilgendorf KI, Perret C, Whyte P, Lees JA. (2014) Bmi1 is required for tumorigenesis in a mouse model of intestinal cancer. Oncogene. doi: 10.1038/onc.2013.333. PMCID: PMC3931743