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Our Research

Cell migration and invasion are essential to embryogenesis, immune system function, wound healing, and cancer dissemination. Cell movement involves cycles of leading edge protrusion and adhesion to the extracellular substrate, followed by de-adhesion and contraction of the cell body and rear. Decades of study have found this movement is highly orchestrated, involving mechanical changes in the actomyosin cytoskeleton and adhesions. Yet we still do not understand the molecular controls that balance and order these structural changes in space and time. Recent advances in proteomics and quantitative imaging now allow scientists and mathematicians to tease out unique and redundant signaling inputs into the motility process. We are using these techniques to understand how extracellular signals impinge on cytoskeletal dynamics and how oncogenic pathway hyperactivation impacts cancer invasion.

The Ras/ERK-MAPK signaling pathway is one of the most commonly activated pathways in solid tumors. We have found that ERK acts on the actin assembly machinery to directly promote rapid and sustained edge protrusion during cell movement. ERK phosphorylates the WAVE Regulatory Complex, which promotes WAVE’s interaction with, recruitment, and activation of the Arp2/3 actin nucleator at the cell edge. This increases actin assembly rates, which generates the pushing force needed to move the membrane forward. We are now characterizing additional ERK pathway inputs into the cytoskeleton and adhesion machinery. We make use of a mix of biochemical approaches involving phosphosite mutants, quantitative live-cell imaging of the cytoskeleton, and optogenetics to discover the function and order of each biochemical input. Through similar mechanistic dissection of additional pathways, we are working to untangle the complex signaling landscape that drives cancer invasion.

Ras and ERK-MAP kinaseRas and ERK-MAP kinase

Our cells are continuously subjected to diverse, fluctuating extracellular cues. Signaling pathways detect and integrate these cues to direct the needed cellular responses: cell division, growth, or movement, for example. Mutations in pathway components cause un-regulated signaling that results in cancer hallmarks. Our lab researches the role such “oncogenic” signaling pathways have in the cell motility process.

We have identified the RAS/ERK-MAPK signaling pathway as one that regulates cell movement. This pathway is canonically known for its role in promoting cell proliferation and survival. Growth factors and oncogenic mutations activate the small GTPase RAS, which signals to the RAF kinase. RAF phosphorylates and activate MEK, which phosphorylates and activates the ERK-MAPK. ERK directly acts on hundreds of substrates to control cell behavior and also signals to the p90 Ribosomal S6 Kinase (RSK). We are determining how ERK and its downstream kinase RSK impinge on the cytoskeletal machinery to effect productive cell motility. Our phospho-proteomic screens and phospho-motif analyses have identified new ERK and RSK phosphorylation events indicative of actin, adhesion, and cell edge regulation. We are characterizing these biochemical signals not as linear conduits, but rather as complex ERK-regulated networks with feedback and pathway cross-talk.

Cell Migration and Invasion

Cell Migration and Invasion

Cell migration and invasion are essential to embryogenesis, immune system function, and wound healing. In contrast, cancer cell invasion is the most significant cause of solid tumor morbidity and mortality. Cell movement can be fibroblast-like (spindle morphology with prominent protrusions, strong adhesions, and protease production), amoeboid (ellipsoid, rapidly deforming morphology with small protrusions and weak adhesions), or somewhere in between. Decades of study have shown that in all cases, the movement involves leading edge protrusion and adhesion to the extracellular matrix substrate, followed by de-adhesion and contraction of the cell body and rear. The mechanical changes in the actomyosin cytoskeleton and adhesions are highly orchestrated. Yet we still do not understand the molecular controls that balance and order these structural changes in space and time. Recent advances in proteomics and quantitative imaging now allow scientists and mathematicians to tease out unique and redundant signaling inputs in the motility process. We are using these techniques to understand how extracellular signals impinge on cytoskeletal dynamics and how oncogenic pathway hyperactivation impacts cancer invasion.

Signaling Controls Cytoskeletal Dynamics

Signaling Controls Cytoskeletal Dynamics

Our lab is dissecting the molecular signaling events that control the structural changes of cell motility. Extracellular cues and oncogenic mutations impinge on cell mechanics to modify the rates and forces controlling motility. We have found that ERK acts on the actin assembly machinery to directly promote rapid and sustained edge protrusion during cell movement. ERK phosphorylates the WAVE Regulatory Complex, which promotes WAVE’s interaction with, recruitment, and activation of the Arp2/3 actin nucleator at the cell edge. This increases actin assembly rates, which generates the pushing force needed to move the membrane forward. We are currently characterizing additional ERK pathway inputs into the cytoskeleton and adhesion machinery. For this, we make use of a mix of biochemical approaches involving phosphosite identification and mutation, quantitative live-cell imaging of the cytoskeleton, and optogenetics to discover the function and order of each biochemical input. Through similar mechanistic dissection of additional pathways, we are working to untangle the complex signaling landscape that drives cancer invasion. We address how activation of these pathways during oncogenesis influences cancer invasion and therapeutic resistance by complementing our in vitro and in situ studies with functional invasion assays involving extracellular matrix and in vivo murine disease models.