Regulation of the Hippo pathway by calcium signaling

The Hippo pathway is a conserved signaling network governing cellular growth, survival and stemness. Mounting evidence suggests that dysregulation of the pathway leads to human health problems, including distorted tissue regeneration and cancer. In order to eliminate these problems, it is critical to understand how the pathway is controlled by tissue homeostatic signals. Recently, we discovered that calcium is an intracellular cue that activates the Hippo pathway to control cell growth and survival in human glioblastoma (GBM) cells (Liu, et al., Oncogene, in press). Elevation of cytosolic calcium by enhancing store-operated calcium entry (SOCE) triggers phosphorylation and activation of Lats1/2, which in turn phosphorylate YAP/TAZ and prevent their accumulation in the cell nucleus. We identified that protein kinase C beta II is a major mediator of calcium-induced Lats1/2 activation. Our studies suggested that calcium is a physiological cue that regulates the Hippo pathway, and that triggering SOCE could be a strategy to target YAP/TAZ in GBM. Currently, we are further characterizing the novel calcium-Hippo pathway connection, aiming at understanding how tissue homeostatic signals control the Hippo pathway and how this pathway could be distorted in cancer and other diseases.

Induction of store operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ.

Zhijun Liu, et al., Oncogene, 2018

Function and regulation of the tumor suppressor protein Merlin

Neurofibromatosis type 2 (NF2) is a genetic disease, in which patients may develop multiple tumors in their nervous system, such as schwannoma, meningioma and ependymoma. The NF2 symptoms usually appear during adolescence or in a person’s early twenties. This disease is caused by defects in a tumor suppressor gene called NF2, which produces a protein called Merlin. How Merlin is activated and functions as a tumor suppressor is not fully resolved. Recently, we discovered that Merlin undergoes novel protein modifications. Our studies suggested that such modifications are important for Merlin activation. Currently, we are functionally and mechanistically examining the novel modifications of Merlin using multiple in vitro and in vivo models.

The role of tumor microenvironment in glioma malignant transformation

Gliomas are major primary brain tumors, of which glioblastomas (GBM) are the most common and aggressive forms. The poor outcome of traditional treatment for these tumors demands targeted therapies based on identified mechanisms that drive tumor development. Molecular pathology has classified GBM into subtypes, among which the mesenchymal (MES) group is the most malignant. It is still not clear how GBM MES differentiation is achieved. Recent studies suggested that the tumor microenvironment contributes to MES differentiation and could be exploited as therapeutic targets. We have established novel GBM mouse models showing enhanced expression of the MES markers. Using these models, we are investigating the tumor microenvironment in GBM MES progression and searching for ways to target this microenvironment for the treatment of GBM.

Our research is supported by:

National Institutes of Health (NIH)

Department of Defense (DoD)

American Association for Cancer Research (AACR)

American Cancer Society (ACS)

Pediatric Cancer Research Foundation (PCRF)

Meghan Rose Bradley Foundation

Four Diamonds Fund of Penn State College of Medicine

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