Cellular structure and function, in healthy and diseased systems, is regulated by the interaction of cells with the underlying and surrounding three-dimensional extra-cellular matrix. These complex biochemical and biomechanical interactions, independently, are well known to regulate tumor progression, invasion and metastasis. For example, the aberrant response of cells to biochemical and biophysical stimuli in metastatic breast cancer is often initiated by engagement of the cytoskeletal machinery. As such, actin interacting proteins are found at the nexus of signaling network crosstalk between biochemical and adhesion-promoting cues. One such example is Mena, a member of the Ena/VASP family of actin regulatory proteins, which has been characterized for aberrant cell-signaling response during invasion and metastasis. However, how the altered signaling network is translated into the mechanical processes, and how are these sub-cellular mechanical processes then converted into whole cell migration in 3D environments remain largely elusive. Here, based on our preliminary data, we hypothesize that increased tumor cell invasiveness in 3D environments, is governed by coupling aberrant molecular level signaling events to molecular, macromolecular and cellular biomechanical processes. Our primary goal in this proposal is to rigorously test our hypothesis by bridging the knowledge gap between in vitro signaling studies at the molecular level, and molecular mechanical and cellular models in 3D, and test the predictions of our models through quantitative experiments in 3D environments. We plan to develop and validate our cellular models using the following three specific aims:
Aim I : Develop an integrated subcellular model of cytoskeletal viscoelasticity and intracellular signaling in native like 3D matrices.
Aim II : Develop a quantitative model of cell migration, in 3D matrices, utilizing results from the subcellular model of Aim I.
Aim III : Validate results of Aims I and II b quantifying how signaling acts cooperatively with cellular mechanics machinery and extracellular matrix properties to regulate cell migration in 3D. All three aims build upon strong preliminary data in both computation and experimental studies and will provide both fundamental insights into the coupling between mechanical and biochemical pathways and integration of information from sub-cellular structures to the cellular level. At the same time, the focus on 3D environments will create new and physiologically relevant knowledge about cellular systems in native like environments. Finally, novel platforms developed through this work will be able to test clinically relevant hypotheses and help in quantitatively understanding complex multi-scale processes during various stages of cancer progression.

Public Health Relevance

The overall goal of this project is to develop new and hypothesis driven multiscale models of cellular structure, signaling, mechanics and organization that in turn regulate cellular migration in vivo and thereby control tumor invasion and metastasis. Successful completion will have the potential to identify novel pathways and mechanisms to control breast and lung tumor development and metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA177799-01
Application #
8477823
Study Section
Special Emphasis Panel (ZEB1-OSR-C (J2))
Program Officer
Couch, Jennifer A
Project Start
2013-04-16
Project End
2018-03-31
Budget Start
2013-04-16
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$652,426
Indirect Cost
$148,103
Name
Boston University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Spill, Fabian; Reynolds, Daniel S; Kamm, Roger D et al. (2016) Impact of the physical microenvironment on tumor progression and metastasis. Curr Opin Biotechnol 40:41-8
Spill, Fabian; Andasari, Vivi; Mak, Michael et al. (2016) Effects of 3D geometries on cellular gradient sensing and polarization. Phys Biol 13:036008
Mak, Michael; Zaman, Muhammad H; Kamm, Roger D et al. (2016) Interplay of active processes modulates tension and drives phase transition in self-renewing, motor-driven cytoskeletal networks. Nat Commun 7:10323
Uzel, Sebastien G M; Amadi, Ovid C; Pearl, Taylor M et al. (2016) Simultaneous or Sequential Orthogonal Gradient Formation in a 3D Cell Culture Microfluidic Platform. Small 12:612-22
Sun, Meng; Spill, Fabian; Zaman, Muhammad H (2016) A Computational Model of YAP/TAZ Mechanosensing. Biophys J 110:2540-50
Spill, Fabian; Weinstein, Zohar B; Irani Shemirani, Atena et al. (2016) Controlling uncertainty in aptamer selection. Proc Natl Acad Sci U S A 113:12076-12081
Cruz, Roberto de la; Guerrero, Pilar; Spill, Fabian et al. (2016) Stochastic multi-scale models of competition within heterogeneous cellular populations: Simulation methods and mean-field analysis. J Theor Biol 407:161-83
Mak, Michael; Spill, Fabian; Kamm, Roger D et al. (2016) Single-Cell Migration in Complex Microenvironments: Mechanics and Signaling Dynamics. J Biomech Eng 138:021004
Mak, Michael; Kim, Taeyoon; Zaman, Muhammad H et al. (2015) Multiscale mechanobiology: computational models for integrating molecules to multicellular systems. Integr Biol (Camb) 7:1093-108
Sun, Meng; Bloom, Alexander B; Zaman, Muhammad H (2015) Rapid Quantification of 3D Collagen Fiber Alignment and Fiber Intersection Correlations with High Sensitivity. PLoS One 10:e0131814

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