Lees Laboratory

Lees

Jacqueline Lees

Research Update

The Lees laboratory studies the mechanisms that underlie tumor development and progression using a combination of mouse and zebrafish models. With the support of the MIT Ludwig Center, we are currently pursuing three metastasis-related projects. 

Dissecting the role of the retinoblastoma protein in cell migration and polarity.

The retinoblastoma protein gene (Rb) was the first known tumor suppressor. Its inactivation is observed in approximately one third of human tumors, with a strong association with tumor types that are highly metastatic. Our analysis of various mouse models has also uncovered a key role for the retinoblastoma protein (pRb) in epithelial cell motility. Initially, we discovered that Rb chimeric embryos frequently displayed eyes open and abnormal ventral body wall suture. These two defects are suggestive of improper tissue closure and commonly associated to mutation in genes involved in cell motility. Subsequently, we found that deletion of Rb impaired the epidermal wound healing response. Each of these defects occurs independent of pRb’s role in E2f and cell cycle regulation.  Instead, we found that Rb is required for the normal cytoskeletal rearrangements that are associated with cell migration. Accordingly, we found that deletion of Rb in keratinocytes reduced their ability to or invade as single cells or migrate as an epithelial sheet. In collaboration with our fellow Ludwig Center member, Frank Gertler, we used time-lapse experiments showed that the Rb deficient cells are slower and less persistent than their wildtype counterparts. Additionally, these experiments, and also data from additional mouse models, show that Rb loss disrupts epithelial cell polarity. Alterations in cell polarity, tissue architecture and cell migration are fundamental facets of tumor progression and metastasis. We are continuing to explore pRb’s role in cell polarity and cell migration to examine how this influences tumor progression and metastasis.  

Dissecting the metastatic drivers of cutaneous melanoma.

The ability of tumor cells to disseminate into distal organs is one of the main challenges to cancer treatment as metastasis accounts for more than 90% of cancer-related deaths. Malignant melanoma is the most aggressive skin cancer, with a high potential for metastasis that is difficult to treat due to acquired resistance to therapy. This provides strong impetus to establish the molecular events that promote malignant melanoma progression and thereby identify potential chemotherapeutic targets. We are investigating the role of a known oncogene, BMI1, in metastatic melanoma. Clinical studies of human melanoma samples have shown that elevated expression of the epigenetic regulator BMI1 correlates with metastatic potential and poor patient outcome. We have used cell-based studies to investigate BMI1’s role in skin melanoma. Our data show that a relatively modest increase in Bmi1 expression is sufficient to induce a metastatic switch in multiple melanoma cell lines. This correlates with changes in the adhesion, invasion, migration and survival properties of the melanoma cells. Accordingly, we found that BMI1 expression had triggered widespread changes in gene expression, including upregulation of regulatory programs strongly associated with poor prognosis in human melanoma patients. Thus, we conclude that BMI1 is a key driver of the metastatic process. By extension of this logic, we hypothesize that BMI1, and its downstream targets, represent key vulnerabilities in metastatic melanoma that are candidates for treatment strategies. We are continuing to dissect the mechanisms by which Bmi1 promotes melanoma metastasis. Additionally, we are assessing Bmi1’s role in mouse models of metastatic melanoma to determine whether inhibition of Bmi1 is sufficient to supress melanoma development and/or metastasis. Taken together, these studies will lead to the identification of genes that are candidate targets for the therapeutic treatment of malignant melanoma, and potentially other metastatic tumor types.

Development of a zebrafish model of metastatic uveal melanoma. 

Uveal melanoma, a cancer derived from nonclassical melanocytes, is the most common primary intraocular cancer, with an estimated 2000 cases diagnosed each year in the United States. Tumors arise in melanocytes found in the choroid, iris, and ciliary body. There is a high success rate in treating the primary tumor, typically with proton beam therapy. However, approximately half of these patients develop liver metastases within 15 years. There are currently no treatment options for metastatic uveal melanoma. Thus, there is an urgent need to develop a vertebrate model for uveal melanoma, to understand the mechanisms of disease initiation and progression and enable the development of new therapeutics. 

Clinical studies have shown that 83% of uveal melanoma tumors have constitutively activating mutations in GNAQ or GNA11, the Gα subunits proteins of G-protein coupled signaling receptors. Through the use of Tol2-mediated transgenesis, we have developed a zebrafish model for human uveal melanoma by expressing mutated human GNA11Q209L or GNAQQ209L under control of the zebrafish melanocyte-restricted mitfa promoter. Several lines have been identified that stably express either of the transgenes, Tg(mitfa:GNAQQ209L) or Tg(mitfa:GNA11Q209L), and show hyper-pigmentation in their skin and eyes. When crossed to a p53 mutant line, these transgenic fish develop rapidly growing, and highly invasive, skin and eye tumors. Through analysis of these fish, and the resulting tumor cell lines, we are probing the mechanisms of tumor development and progression.