Epigenetic regulators in cancer.  It is well established that deregulation of one or more epigenetic regulators is critical in tumor development or progression. The Lees Lab is currently studying two epigenetic regulators, PRMT5 and BMI1, linked to cancer development and progression, but have important implications on stem cell function. 

PRMT5 is an arginine methyltransferase that mediates most of the symmetric dimethylarginine (SDMA) modifications in mammalian cells.  Its expression is upregulated in a wide variety of human tumors and correlates with poor prognosis.  The Lees Lab identified PRMT5 through an in vivo shRNA depletion screen for genes essential for glioma development, showing that PRMT5 deficiency suppresses proliferation or induces apoptosis in gliomas and other tumor types. We established that PRMT5-dependent tumors are addicted to splicing and that PRMT5 deficiency promotes the inclusion of detained introns in proliferation-associated genes, inducing of senescence and/or apoptosis, depending on the context.  Ongoing projects include:

• Investigating the molecular mechanisms by which PRMT5 regulates splicing in normal and tumor cells, and
• Analyzing of the cellular determinants of sensitivity or resistance to PRMT5 small molecule inhibitors.

BMI1 is a component of the polycomb repressive complex 1 (PRC1), which was originally identified as a regulator of developmental patterning.  BMI1 is expressed in adult stem cells, and not in post-mitotic tissues. BMI1 expression is upregulated in many different human cancer types and correlates with poor prognosis. The Lees Lab is using a combination of cell-based approaches and sophisticated mouse models to understand the contribution of BMI1 to tumorigenesis. We have shown that the absence of BMI1 during murine development allows for initiation of lung or intestinal tumors, but blocks tumor progression at an early stage due to depression of the CDKN2a tumor suppressor locus, impairing the self-renewal and proliferative capacity of cancer stem cells.  Additionally, in the context of melanoma, we have shown that BMI1 is a critical determinant of metastatic potential and resistance to chemotherapies.  Collectively, these studies raise the possibility that BMI1 inhibition could provide a mechanism to suppress tumor progression and metastasis by targeting cancer stem cells, a holy grail in the cancer field.  Ongoing projects include:

• Establishing the consequences of BMI1 loss in normal adult versus cancer stem cells, and
• Determining the effect of BMI1 loss on the maintenance and progression of pre-existing tumors, with the goal of modeling therapeutic treatment.