Edna Cukierman, PhD
Office Phone: 215-214-4218
Lab Phone: 215-214-4219
How do tumor-associated ECMs activate normal fibroblasts?
Adhesion structures formed by fibroblasts cultured within mesenchymal cell-derived 3D matrices are categorically distinct from both the focal and the fibrillar adhesions traditionally studied in 2D cultures. These in vivo-like α5 β1-integrin positive “3D-adhesions” contain many proteins found in focal adhesions, such as paxillin and vinculin, but not others such as constitutively activated focal adhesion kinase (FAK). Integrin-associated adhesions (e.g., 3D-adhesions) are a primary point of communication between ECMs and cells, and thus might be important for late stage stromal-dependent reprogramming of cell growth where expression levels of desmoplastic markers such as alpha-smooth muscle actin (α-SMA), are increased. Consequently, we are analyzing these interactions with the goal to uncover staged matrix-induced fibroblastic differentiation during tumor development and progression.
How does fibroblast matrix induce tumor progression?Video: Invasive cell motility through tumor-associated 3D ECMs under PI3K and/or β1-integrin inhibition This content requires the Adobe Flash Player.
Video: Invasive cell motility through tumor-associated 3D ECMs under PI3K
and/or β1-integrin inhibition - Montage of six hour time-lapse videos depicting
MDA-MB-231 cells invading through tumor-associated 3D ECMs (top left) in the
presence of 10 nM Wortmannin (top right), 50 μg/ml mAb13 (bottom left) or a
combination of both mAb13 and 10 nM Wortmannin (bottom right).
Tumor cell migration and metastasis can occur by multiple mechanisms (e.g., epithelial-mesenchymal transition using ‘mesenchymal’ strategies, or mesenchymal-amoeboid transition using ‘amoeboid’ strategies of cell invasion). Mechanisms for these strategies are based on different signaling pathways, which are directly induced by the stromal microenvironment and are clearly distinguished in vivo and in vitro by various cell morphologies. We have sought to define how 3D matrices, produced by early- versus late-stage fibroblasts, condition tumor cell invasion and signaling.Top
Development of New Technologies for the Use of Tumor-Associated Fibroblasts and Mesenchymal 3D Matrices as a Resource for the Scientific Community
We believe that fibroblast-derived 3D matrices have value as in vitro drug screening platforms and that the nature of fibroblasts within a mesenchymal tumor-associated stroma can change the invasive behavior of tumors. We have developed a suite of technological tools which serve the scientific community for studies of stroma-induced tumorigenesis. Our expertise in these areas have initiated pilot studies aimed at developing medium- and low-throughput assays to measure the morphology and invasive behavior of tumor cells within staged stromal matrices. In the future, we hope to implement the throughput assays to test matrix-induced drug responses, which will allow screening microenvironmental settings (+/- tumor-associated fibroblasts), for cancer cell permissiveness (e.g., invasiveness). Results from these studies could provide a unique opportunity to tailor or select cancer- and patient-specific therapeutic regimens.Top