Funded Grants

The role of the tumor suppressor gene PTEN in neural stem cell biology and brain tumor development

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in humans. Clinically, GBM can be divided into two groups: primary and secondary GBM. Primary GBM arises quickly without prior sign of symptoms and has a median survival of less than a year. In contrast, the secondary GBM develops progressively from low-grade astrocytoma over a period of 5-10 years. Sadly, the prognosis for primary GBM has not changed during the past two decades due to a lack of insight into the molecular basis of the diseases and appropriate animal models. The tumor suppressor gene PTEN is a promising candidate for being involved in human GBM. PTEN is frequently mutated in up to 40% of GBMs and alterations in the cellular machinery controlled by PTEN are known to be associated with many human types of cancers.

Recent studies suggest that cancers may be viewed as an aberrant organ initiated by “cancer stem cells”. Analogous to normal stem cells, cancer stem cells have the capacity for indefinite proliferation and the ability to give rise to new abnormal tissues through self-renewal and differentiation. The key difference between normal and cancer stem cells may be due to the disregulated stem cell self-renewal and proliferation/survival, through accumulated mutations. The fact that cells from human GBMs resemble immature undifferentiated brain cells morphologically, and share some of the biological markers present in the neural stem cells has raised an interesting hypothesis that the origin of primary GBM may be mutated forms of neural stem/progenitor cells in the adult brain.

Analyzing animals with a brain-specific PTEN deletion, we demonstrated that the PTEN tumor suppressor negatively regulates neural stem/progenitor cell proliferation, survival, and self-renewal. Interestingly, the differentiation program of PTEN deficient neural stem cell is largely undisturbed, which fits well with the concept of “cancer stem cells”. However, few experiments have conducted to test whether PTEN is also important in regulating adult neural stem cells, a stage when primary GBM develops. We will address this question by specifically deleting PTEN in areas of the adult brain that harbor neural stem cells. We will follow the fate of the progenies derived from PTEN deficient stem cells and assess their potential to become cancerous cells.

GBM development is a multi-step process, involving different genetic abnormalities. To understand how PTEN will collaborate with other important oncogenes and tumor suppressor genes in regulating brain tumor formation, we plan to generate animal models with a combination of PTEN deletion and other genetic alterations. As an example of our general approach, we will delete both PTEN and NF1 tumor suppressor genes in the mouse brain, which will perturb the two most common signaling pathways regulated by growth factors and their receptor tyrosine kinases.

Mapping the molecular events leading to GBM will provide more specific and efficient targets to cancer therapy. To this end, we have used mice with brain PTEN deletion to evaluate the potential therapeutic benefit of drugs specifically inhibiting PTEN controlled signaling pathways. PTEN negatively regulates mTOR (mammalian Target Of Rapamycin), a master regulator of cellular growth. We showed that PTEN mutated brains are hypersensitive to rapamycin, an inhibitor of mTOR. Significantly, rapamycin treatment led to partial rescue of the abnormalities associated with PTEN deletion, such as progressive increase in brain size and brain pressure, altered brain structure, and subsequent lethality. We will continue this effort and further evaluate the efficacy of single and combined treatment procedures. It is our hope that this basic research will provide both insights into molecular mechanisms of GBM and valuable models for evaluating potential treatments.