Unique biomechanical and biophysical features of cancer cells represent a relatively untapped potential source of biomarkers for the detection, diagnosis and monitoring of therapeutic response in cancer patients. These distinct cancer cell phenotypes may integrate a number of the molecular abnormalities driving cancer into discrete, quantifiable biomarkers that could, in principle, be more consistent and straightforward to assess than the complex genetic landscape in this disease. It has recently been shown that cancer cell lines from numerous tissues in suspension exhibit resistance to brief pulses of high level fluid shear stress (FSS) compared to normal or benign epithelial cells. This phenotype reflects signaling through at least several common oncogenic pathways. The objective of this proposal is to determine if resistance to FSS is a biomarker with clinical diagnostic potential in animal models of prostate cancer and tissue from human melanoma subjects. The central hypothesis of this proposal is that resistance to fluid shear stress is a conserved biophysical property of cancer cells that is associated with disease progression and can be used to predict response to therapy. The rationale for the proposed research is that once it is determined that FSS resistance is associated with pathologic progression of disease, and/or response to molecularly targeted therapies these findings can be translated into a novel clinical diagnostic paradigm for prognostic assessments or predicting early failure or prolonged response not possible with conventional approaches.
The specific aims of this proposal are: 1) Determine if resistance to FSS is associated with prostate cancer progression in animal models;and 2) Determine if resistance to FSS is associated with drug sensitivity in tissue from human melanoma subjects. The contribution of this proposal will be significant because it will test the concept that FSS resistance is a clinically relevant biomarker worthy of further study and development. This proposal employs a simple microfluidic assay to measure FSS resistance in two separate experimental paradigms, one animal-based, one in human tissue. It is anticipated that increased FSS is associated with disease progression and decreased FSS corresponds to drug sensitivity. The proposed research is innovative because it represents a rapid and simple means to assess the response of a population of cancer cells to mechanical force (FSS) in suspensions that can be readily prepared from clinical specimens. The transformative potential of this work is that it may provide an alternative paradigm to molecular diagnostics.
The proposed research is relevant to the mission of the NCI because it seeks to develop a novel clinical diagnostic paradigm based on measurement of a biophysical biomarker, resistance to fluid shear stress, in cancer cells. These studies will have broad applicability to many types of cancer, but will most immediately benefit prostate cancer, in which there is a significant unmet need for prognostic biomarkers, and melanoma, where FSS resistance may be used to predict therapeutic response. This approach is a substantive departure from established techniques and has distinct advantages: speed, simplicity, applicability to clinically obtainable specimens, and assessment of cell populations that favor its translational potential.
|Chivukula, Venkat Keshav; Krog, Benjamin L; Nauseef, Jones T et al. (2015) Alterations in cancer cell mechanical properties after fluid shear stress exposure: a micropipette aspiration study. Cell Health Cytoskelet 7:25-35|