Research Overview
Research Overview
Development of multicellular organisms requires the precise patterning of cells, which must interpret and respond to specific molecular cues. Cells assume distinct identities, initiate an appropriate differentiation programs, and generate three dimensional, spatially organized tissues. The same pathways that instruct normal development are dysregulated in cancer cells to facilitate rapid proliferation (hyperplasia), overcome restrictions on tissue size and organization (dysplasia), and gain migratory capacity to leave the primary tumor site and seed new tumor growth at distant sites (metastasis). Our lab investigates the regulation of morphogenetic cell processes by intracellular pH (pHi) during normal development and diseases, including cancer.
We investigate how this fundamental and understudied property of cells can shape and influence tissues using a broad toolkit including Drosophila genetics, cell biological techniques, and biochemical analysis of proteins using fruit flies at different stages of development and cultured mammalian cells.
Project 1: How is normal development regulated by intracellular pH dynamics?
Using a fluorescent protein pH biosensor, we can detect pH gradients in developing tissues, such as the wing disc (left, precursor to the adult wing) and the eye disc (right, precursor to the adult eye). However, the significance and function of these gradients is completely unknown. We will begin to understand more about these pH gradients by asking the following questions:
1. which ion transporters regulate pHi in developing Drosophila tissue?
2. what are the functional consequences of disrupting these gradients during development?
3. what are the proteins that sense and respond to changes in intracellular pH?
Project 2: How does the increased pHi common in cancer enable tumorigenic properties and metastasis?
Cancer is often considered a disease of “development gone wrong”. Increased pHi is an emerging hallmark of cancer cells, which is hypothesized to promote cancer progression and metastasis. In the image on the right, we have shown a genetic interaction where overexpression of Dnhe2 (to increase pHi) enhances the metastatic phenotype of RasV12. We will explore this interaction by asking the following questions:
1. in oncogene-transformed tissue, is pHi higher in invasive cells than in the primary tumor? Does Dnhe2 co-expression enhance this effect?
2. can increased H+ efflux can generally enhance oncogene-mediated phenotypes?
3. what are temporal and spatial pHi dynamics during tumorigenesis and metastasis?
