In recent years, cancer has surpassed heart disease as the leading cause of death among Americans who are younger than 85 years. In particular, breast cancer is the second leading cause of cancer-related deaths in the United States and often leads to secondary metastatic tumor sites in the bone, lungs, and liver. Tumor progression and metastasis involve two basic cellular processes: cell migration through interstitial tissues and cell division at the primary tumor and distal metastatic sites. During these processes, cells are subjected to complex three-dimensional environments that vary both biologically and physically. In this proposal, the overall objective is to evaluate how cell volume and polarity are regulated during migration and division when cells are subjected to varying degrees of physical confinement and/or matrix elasticity. We will use a combination of microfabricated devices, cell engineering techniques, and high-resolution phase contrast and laser scanning confocal timelapse microscopy to accomplish this objective. We hypothesize that the physical properties of the breast cancer cell microenvironment regulate cell volume and polarity during migration and the cell cycle.
Two specific aims are proposed to address this hypothesis: (1) Elucidate the molecular mechanisms of cell migration and volume regulation in response to osmotic shock in confined microenvironments;and (2) Evaluate the effects of confinement and microenvironment elasticity on the spatial and temporal regulation of the cell cycle. The long-term goals of this project are to (1) contribute to our understanding of how cell volume and polarity are regulated during migration and division in confined microenvironments on a basic science level;(2) provide knowledge that could ultimately be used in the development of novel treatment strategies to control breast cancer cell proliferation and metastasis, (3) provide me with experimental and theoretical training in the field of cancer biophysics, which will be necessary for my future career as an independent researcher;and (4) contribute to my career development, through training on grant and manuscript writing, mentoring of graduate and undergraduate students, public speaking, and networking with future collaborators. Activities planned under the fellowship include original research (60% of time);manuscript preparation (10%);grant writing (10%);formal course work on Cancer Biology, Research Leadership, and Responsible Conduct of Research (5%);attendance at professional meetings (5%);participation in laboratory group meetings of our lab and collaborators (5%);mentoring Ph.D. and undergraduate students (2%);attendance at departmental seminars (2%);and participation in a postdoctoral journal club (1%). In completing the activities proposed under this fellowship, I will be prepared to begin an independent faculty career and will have the knowledge base and skill set to address biological problems relating to cancer using bioengineering strategies. !
Alterations in cell division and migration are hallmarks of tumor progression and the metastatic process of cancer cells. In the tumor microenvironment, or during migration through tissues in metastasis, cancer cells experience varying degrees of physical confinement and matrix elasticity, due to the complex environment created by neighboring cells and the extracellular matrix, therefore, it is critical to study cellular processs in three-dimensional environments, rather than in flat, stiff petri dishes that can lead to non-physiological cell behavior. In this proposal, the overall objective is to evaluate how cell migration and division are regulated when cells are subjected to varying degrees of physical confinement and matrix elasticity.
|Stroka, Kimberly M; Wong, Bin Sheng; Shriver, Marey et al. (2017) Loss of giant obscurins alters breast epithelial cell mechanosensing of matrix stiffness. Oncotarget 8:54004-54020|
|Shriver, M; Stroka, K M; Vitolo, M I et al. (2015) Loss of giant obscurins from breast epithelium promotes epithelial-to-mesenchymal transition, tumorigenicity and metastasis. Oncogene 34:4248-59|
|Stroka, Kimberly M; Jiang, Hongyuan; Chen, Shih-Hsun et al. (2014) Water permeation drives tumor cell migration in confined microenvironments. Cell 157:611-23|
|Stroka, Kimberly M; Konstantopoulos, Konstantinos (2014) Physical biology in cancer. 4. Physical cues guide tumor cell adhesion and migration. Am J Physiol Cell Physiol 306:C98-C109|
|Stroka, Kimberly M; Gu, Zhizhan; Sun, Sean X et al. (2014) Bioengineering paradigms for cell migration in confined microenvironments. Curr Opin Cell Biol 30:41-50|
|Raman, Phrabha S; Paul, Colin D; Stroka, Kimberly M et al. (2013) Probing cell traction forces in confined microenvironments. Lab Chip 13:4599-607|
|Hung, Wei-Chien; Chen, Shih-Hsun; Paul, Colin D et al. (2013) Distinct signaling mechanisms regulate migration in unconfined versus confined spaces. J Cell Biol 202:807-24|