Cell motility is essential to embryogenesis, wound healing, and cancer cell metastasis. During this process, iterative cycles of edge protrusion and retraction, adhesion to the extracellular matrix, and cell body contraction propel cells forward.
The Mendoza laboratory addresses the mechanisms and biological significance of signaling pathways that control cell motility.
We are using the following three approaches:
1) Biochemical mechanisms
2) Quantitative image analysis
3) Cancer-relevant scenarios
(1) Biochemical mechanisms of motility
Signaling pathways are not linear conduits, but rather complex networks with multiple points of input, output, feedback, and cross-talk with other pathways. We are untangling these networks by elucidating the mechanisms by which the individual pathways control actomyosin and adhesion dynamics and then using biochemical screens and functional knowledge to develop hypotheses on sources of molecular and functional compensation.
Ras and ERK-MAP kinase. We have identified the Ras/ERK-MAPK signaling pathway as one that regulates cell motility. Growth factors and oncogenic mutations activate the small GTPase Ras, which signals to the ERK-MAPK and the ERK-regulated kinase p90 Ribosomal S6 Kinase (RSK). Through biochemical and imaging approaches, we are determining how ERK and its downstream kinase RSK contribute to actin, adhesion, and cell edge dynamics and how improper regulation contributes to a variety of human diseases, including cancer and developmental disorders.
Signaling Crosstalk and Compensation. Signaling pathways are not linear conduits, but rather complex networks with multiple points of output, feedback, and cross-talk with other pathways. We are untangling these networks by elucidating the mechanisms by which the oncogenically-activated pathways control actomyosin and adhesion dynamics and then developing hypotheses on sources of molecular and functional compensation.
The mechanical changes necessary for cell motility are spatially and temporally coordinated. Extracellular cues and oncogenic mutations impinge on cell mechanics to modify migration rate, persistence, and directionality. We are uncovering points of unique and redundant regulation by imaging steady-state migrating cells and quantifying fluctuations in molecular activities (protein localization, actin, adhesion, and cell edge dynamics) with spatiotemporal precision. We use statistical analysis to discern the function of specific kinases amongst the background of multiple operative signaling pathways.
(3) Disease relevance
Cell invasion is fundamental to tissue morphogenesis during development and tumor metastasis. Invading cells overcome the structural restraints of tissue organization and migrate as single cells, chains, clusters, or sheets through the stroma and into the vasculature in the case of metastasis. Efforts to therapeutically target invasion are limited by a lack of mechanistic insight in how motility morphodynamics are regulated by signaling pathways. We complement our in vitro and in situ studies with functional assays of invasion assays involving ex vivo extracellular matrix and in vivo murine disease models. Current models include those of breast and lung cancer.