The Migration Networks Project is designed to understand how key steps in the onset and progression of metastatic disease are regulated. Our overall goal is to identify new targets for therapeutic intervention in metastatic disease, the most frequent cause of mortality in cancer patients.
We focus on four general aspects of invasion and metastasis: motility responses to growth factor stimulation, acquisition of a motile phenotype during epithelial to mesenchymal transition (EMT), dissemination of metastasis to the CNS and acquisition of resistance to therapy. We will generate quantitative data to describe cell behavior during EMT and growth factor-elicited motility. The status of signaling pathways, gene expression and alternative splicing will be interrogated and used to take a systems approach to develop computational models to elucidate how molecular networks are dysregulated to yield aggressive cell behavior. The models will include physico-chemical mechanistic simulations, statistical models for signal-response relationships, and topological models that integrate transcriptional, signaling and cytoskeletal regulatory processes. The experiments will employ mammary epithelia cells, breast cancer cells, xenografts and syngeneic tumor models, and lymphoma. We therefore expand upon on our experience with mammary carcinoma during the last funding period and integrate a powerful new lymphoma model for in vivo gene discovery. The work in this program dovetails well with the mitogenesis and DNA damage/therapeutics programs. All three programs consider ErbB signaling and both this and the therapeutics program specifically examine breast cancer and lymphoma cells. The three programs also all consider the problem of acquired resistance to chemotherapy during cancer progression. Reagents, data, ideas and hypotheses will flow frequently between the three Projects.
Specific Aim 1 - Application of biophysical cell migration and biochemical signaling models to Mena/EGFR synergy in tumor cell motility dysregulation
Specific Aim 2 - Signaling network models for EMT-dependent growth factor-induced motility
Specific Aim 3 - Integrated transcriptomic and proteomic topology modeling of EMT dysregulation
Specific Aim 4 - Systems analysis of motility dysregulation in metastasis and chemotherapeutic resistance
Goswami S, Philippar U, Sun D, Patsialou A, Avraham J, Wang W, Di Modugno F, Nistico P, Gertler FB, Condeelis JS. Identification of invasion specific splice variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo. Clin Exp Metastasis. 2009;26(2):153-9.
Joslin EJ, Opresko LK, Wells A, Wiley HS, Lauffenburger DA. EGF-receptor-mediated mammary epithelial cell migration is driven by sustained ERK signaling from autocrine stimulation. J Cell Sci 2007 Sep 25; 120(20): 3688-99.
Kharait S, Hautaniemi S, Wu S, Iwabu A, Lauffenburger DA, Wells A. Decision tree modeling predicts effects of inhibiting contractility signaling on cell motility. BMC Syst Biol. 2007 Jan 29;1:9.
Kim HD, Guo TW, Wu AP, Wells A, Gertler FB, Lauffenburger DA. Epidermal growth factor-induced enhancement of glioblastoma cell migration in 3D arises from an intrinsic increase in speed but an extrinsic matrix- and proteolysis-dependent increase in persistence. Mol Biol Cell. 2008 Oct;19(10):4249-59.
Kumar N, Afeyan R, Kim HD, Lauffenburger DA. Multi-pathway model enables prediction of kinase inhibitor cross-talk effects on migration of HER2-overexpressing mammary epithelial cells. Mol Pharmacol. 2008 Jun;73(6):1668-78.
Kumar N, Zaman MH, Kim HD, Lauffenburger, DA. A high-throughput migration assay reveals HER2-mediated cell migration arising from increased directional persistence. Biophys J. 2006 Aug 15;91(4):L32-4.
Lacy-Hulbert A, Smith AM, Tissire H, Barry M, Crowley D, Bronson RT, Roes JT, Savill JS, Hynes RO. Ulcerative colitis and autoimmunity induced by loss of myeloid alphav integrins. Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15823-8.
Philippar U, Roussos ET, Oser M, Yamaguchi H, Kim HD, Giampieri S, Wang Y, Goswami S, Wyckoff JB, Lauffenburger DA, Sahai E, Condeelis JS, Gertler FB. A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis. Dev Cell. 2008 Dec;15(6):813-28.
Pino MS, Balsamo M, Di Modugno F, Mottolese M, Alessio M, Melucci E, Milella M, McConkey DJ, Philippar U, Gertler FB, Natali PG, Nistico P. Human Mena+11a isoform serves as a marker of epithelial phenotype and sensitivity to epidermal growth factor receptor inhibition in human pancreatic cancer cell lines. Clin Cancer Res. 2008 Aug 1;14(15):4943-50.
Robinson BD, Sica GL, Liu YF, Rohan TE, Gertler FB, Condeelis JS, Jones JG. Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res. 2009 Apr 1;15(7):2433-41.
Sobolev O, Stern P, Lacy-Hulbert A, Hynes RO. Natural killer cells require selectins for suppression of subcutaneous tumors. Cancer Res. 2009 Mar 15;69(6):2531-9.
Wong SY, Crowley D, Bronson RT, Hynes RO. Analyses of the role of endogenous SPARC in mouse models of prostate and breast cancer. Clin Exp Metastasis. 2008;25(2):109-18.
Wong SY, Haack H, Kissil JL, Barry M, Bronson RT, Shen S, Whittaker CA, Crowley D, Hynes RO. Protein 4.1B suppresses prostate cancer progression and metastasis. Proc Natl Acad Sci U S A. 2007 Jul 31; 104(31): 12784-9.
Xu L, Shen S, Subramanian A, Ross K, Brunet JP, Ramaswamy S, Mesirov JP, Hynes RO. Gene expression changes in an animal melanoma model correlate with aggressiveness of human melanoma metastases. Mol Cancer Res. 2008 May;6(5):760-9.
Zaman, MH, Kamm RD, Matsudaira P, Lauffenburger DA. Computational model for cell migration in three-dimensional matrices. Biophys J. 2005 Aug;89(2):1389-97.
Zaman MH, Matsudaira P, Lauffenburger DA. Understanding effects of matrix protease and matrix organization on directional persistence and translational speed in three-dimensional cell migration. Ann Biomed Eng. 2007 Jan;35(1):91-100.
Zaman MH, Trapani LM, Sieminski AL, Mackellar D, Gong H, Kamm RD, Wells A, Lauffenburger DA, Matsudaira P. Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis. Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10889-94.