A treatment that could stop cancer cells from moving away from the primary tumor could prevent metastases and extend the life of cancer patients. However, such a treatment that stops cancer cell migration does not yet exist. Despite intense research efforts in the past five decades, 90% of the current cancer related deaths are still due to metastases. Systematic attempts to prevent cancer metastases have targeted mainly the context of cancer cell migration, by altering cell-cell interactions, inhibiting the activity of enzymes required to degrade matrix, or altering cancer cell proliferation. Despite the fact that these treatments have shown great potential when tested in model systems, they had only limited practical success on blocking metastases. Two limitations of current model systems for studying cell migration are significant in this respect. First, most assays report the average migration of a large population of cells, and cannot capture the behavior of outliers, single cells that are ultimately responsible for metastases. Second, many assays alter cellular processes which in turn indirectly modulate cell motility;however, the intrinsic motility potential of cancer cells remains the same and becomes manifest in cells that escape or adapt to the new conditions. In this context, new experimental models for studying cancer cell migration are needed that can quantitatively measure the intrinsic motility of cells and the modulation of cancer cell migration by cell-cell interactions, matrix degradation, or substrate. We have recently made the surprising observation that cancer cells from various cell lines are able to move unexpectedly fast and persistent for several hours in one direction, when mechanically constrained in microfabricated capillaries with dimensions smaller than the cells. This particular behavior may be relevant to several in vivo situations where the migration of the cancer cells in tissues is favored along preexisting paths in the form of blood or lymphatic vessels, collagen fibers, or white matter tracts. We believe that our new experimental system could reveal critical characteristics for cancer cell migration and could enable us to probe in quantitative ways many of the interactions known to modulate cancer cells migration. To validate the potential of the new tools and demonstrate their use for quantitative insights into cancer cell migration we propose: 1) to quantitatively measure the effects of cell-cell, cell-substrate, and cell-matrix interaction on the vectorial motility of individual cancer cells inside microcapillaries;2) to quantitatively measure the modulation of cancer cell vectorial motility by heterogeneous cell-cell interactions. This proposed work will form the basis for future studies aiming at characterizing motility in cancer cells from patients, as a prerequisite for enabling new approaches for evaluating the prognosis of cancer patients, screening new drugs for the therapy of metastases in cancer patients, or personalized cancer treatment.

Public Health Relevance

More than 90% of the cancer related deaths are due to metastases. Metastases are formed by cells that leave the primary tumor, spread in the entire body and colonize distant organs like liver, lungs, brain, or bones. One major challenge in understanding the complexity of cancer cell migration is the accurate measuring of cell motility and quantification of its modulation by other cellular processes: e.g. motility, invasion, adhesion, cell- cell communication. In this proposal we will validate new microfluidic tools for the study of cancer cell motility. Understanding the migration abilities of cancer cells could help designing novel approaches for stopping their migration from the primary tumor and into tissues. This could prevent metastases before they occur, transforming cancer into a chronic disease with which the patient can live a longer period of time.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA135601-02
Application #
8004921
Study Section
Enabling Bioanalytical and Biophysical Technologies Study Section (EBT)
Program Officer
Ossandon, Miguel
Project Start
2009-12-14
Project End
2012-05-30
Budget Start
2010-12-01
Budget End
2012-05-30
Support Year
2
Fiscal Year
2011
Total Cost
$186,714
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Dang, Irène; Linkner, Joern; Yan, Jun et al. (2017) The Arp2/3 inhibitory protein Arpin is dispensable for chemotaxis. Biol Cell 109:162-166
Wong, Ian Y; Javaid, Sarah; Wong, Elisabeth A et al. (2014) Collective and individual migration following the epithelial-mesenchymal transition. Nat Mater 13:1063-71
Yan, Jun; Irimia, Daniel (2014) Stochastic variations of migration speed between cells in clonal populations. Technology (Singap World Sci) 2:185-188
Desai, Salil P; Bhatia, Sangeeta N; Toner, Mehmet et al. (2013) Mitochondrial localization and the persistent migration of epithelial cancer cells. Biophys J 104:2077-88
Ritch, James J; Valencia, Antonio; Alexander, Jonathan et al. (2012) Multiple phenotypes in Huntington disease mouse neural stem cells. Mol Cell Neurosci 50:70-81
Scherber, Cally; Aranyosi, Alexander J; Kulemann, Birte et al. (2012) Epithelial cell guidance by self-generated EGF gradients. Integr Biol (Camb) 4:259-69
El-Haibi, Christelle P; Bell, George W; Zhang, Jiangwen et al. (2012) Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy. Proc Natl Acad Sci U S A 109:17460-5
Smolen, Gromoslaw A; Zhang, Jianmin; Zubrowski, Matthew J et al. (2010) A genome-wide RNAi screen identifies multiple RSK-dependent regulators of cell migration. Genes Dev 24:2654-65
Wolfer, Anita; Wittner, Ben S; Irimia, Daniel et al. (2010) MYC regulation of a ""poor-prognosis"" metastatic cancer cell state. Proc Natl Acad Sci U S A 107:3698-703
Irimia, Daniel; Toner, Mehmet (2009) Spontaneous migration of cancer cells under conditions of mechanical confinement. Integr Biol (Camb) 1:506-12