Cell migration is inherently a physical process, guided by extracellular and intracellular chemical gradients, physical forces and structural architectures. In this proposal, we are answering the question: How do the physical components of the tumor microenvironment contribute to metastatic migration? Our overarching hypothesis is that specific chemical gradients created by cells within the 3D tumor microenvironment and changes in extracellular matrix (ECM) enable and enhance cell migration during metastasis. We will employ concepts and tools from the physical sciences to dissect the complex chemical and physical microenvironmental factors guiding cell migration during metastasis. To do this, we propose to use well-defined model tissue constructs where the cellular environment is tightly controlled to describe and measure a set of physical parameters that define the invasive behavior of tumor cells;the motility of a cell (Diffusivity, D), chemotactic response (Persistence, P), and the propulsive force (F). These measurements will be made of well-characterized cell lines and breast cancer patient-derived primary tumor cells as a function of the chemical and mechanical microenvironments, with and without targeted therapeutics. These parameters will be correlated with disease stage, clinical classification of invasiveness and time to recurrence and will in turn be fed back to our quantitative models to inform and refine them. Measurement of these parameters will lead to a more complete description of the physical regulators of metastatic migration, and the identification of novel targets for therapeutics which disrupt metastatic cell migration. This proposal will answer the following questions: Does cellular physical force generation correlate with the metastatic tumor cell potential? Does the chemical microenvironment created by surrounding immune cells and vascular cells control the metastatic migratory phenotype? Does the increased mechanical stiffness of solid tumor ECM enable the migratory phenotype via increases in cell force? What is the role of microtubule dynamics and selected tubulin posttranslational modifications in the process of cell migration in response to distinct ECM chemomechanical cues? How do microtubule-targeting chemotherapeutic drugs modulate these behaviors and how is individual patient sensitivity to therapy affected by the interplay between ECM chemical gradients and mechanical forces and resident tumor cells? This work represents a paradigm shift over traditional 2D cell migration studies as it underscores the need to systematically de-convolve the complex 3D chemical and mechanical microenvironmental conditions affecting tumor cell migration. With this proposal we are integrating novel, quantitative methodologies from the discipline of physical sciences to systematically and robustly answer fundamental and complex questions in cancer biology and molecular oncology. Our work promises to understand the role of microenvironment in metastasis and has the potential of """"""""translating"""""""" this knowledge into actual clinical gains.

Public Health Relevance

This PS-OC brings together expert teams from the fields of physics, nano and microfabrication, engineering and cancer biology to develop novel trans-disciplinary approaches to better understand the complexity of cancer metastasis, the aspect of cancer that directly leads to patient morbidity and mortality. Approaches developed by physical scientists will be focused on the study of cancer. Our studies aim to identify novel mechanisms used by cancer cells, but not normal cells, for growth and metastasis to distant body sites. These new mechanism provide novel drug targets, that aim towards arresting cancer metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cornell University
United States
Zip Code
Ariza-Nieto, Magnolia; Alley, Joshua B; Samy, Sanjay et al. (2018) Circulating miR-148a associates with sensitivity to adiponectin levels in human metabolic surgery for weight loss. Endocr Connect :
Song, Young Hye; Warncke, Christine; Choi, Sung Jin et al. (2017) Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells. Matrix Biol 60-61:190-205
Carey, Shawn P; Martin, Karen E; Reinhart-King, Cynthia A (2017) Three-dimensional collagen matrix induces a mechanosensitive invasive epithelial phenotype. Sci Rep 7:42088
Huang, Yu Ling; Segall, Jeffrey E; Wu, Mingming (2017) Microfluidic modeling of the biophysical microenvironment in tumor cell invasion. Lab Chip 17:3221-3233
McDowell, G S; Philpott, A (2016) New Insights Into the Role of Ubiquitylation of Proteins. Int Rev Cell Mol Biol 325:35-88
Carey, Shawn P; Goldblatt, Zachary E; Martin, Karen E et al. (2016) Local extracellular matrix alignment directs cellular protrusion dynamics and migration through Rac1 and FAK. Integr Biol (Camb) 8:821-35
Dimonte, Alice; Adamatzky, Andrew; Erokhin, Victor et al. (2016) On chirality of slime mould. Biosystems 140:23-7
Li, Jiahe; Sharkey, Charles C; Wun, Brittany et al. (2016) Genetic engineering of platelets to neutralize circulating tumor cells. J Control Release 228:38-47
Wang, Suming; Blois, Anna; El Rayes, Tina et al. (2016) Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment. Sci Transl Med 8:329ra34
Mittal, Vivek (2016) Epithelial Mesenchymal Transition in Aggressive Lung Cancers. Adv Exp Med Biol 890:37-56

Showing the most recent 10 out of 197 publications