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Abstract:
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The broad objective of this research is to examine the relationship between the cellular micromechanical environment and disease progression in cancer . The mechanical stiffness of cancerous tissue is a key feature that distinguishes it from normal tissue and thus facilitates its detection clinically . While numerous inroads have been achieved toward elucidating molecular mechanisms that underlie diseases such as cancer , quantitative characterization of associated cellular mechanical properties and biophysical attributes remains largely incomplete . To this end , the present research provides insight into the following questions : (1 ) What is the effect of extracellular matrix (ECM ) stiffness and architecture on internal cancer cell rheology and cytoskeletal organization ? (2 ) What are the integrated effects of ECM stiffness and cell metastatic potential on the intracellular rheology and morphology of breast cancer cells ? (3 ) What are the integrated effects of ECM stiffness , ECM architecture , and cell metastatic potential on the motility of breast cancer cells ? To examine these phenomena , the present research utilizes a multidisciplinary engineering approach that integrates experimental rheology , theoretical mechanics , confocal microscopy , computational algorithms , and experimental cell biology . Briefly , genetically altered cancer -mimicking cells are cultured within synthetic ECMs of varying mechanical stiffness and structure , where they are then observed using time -lapsed confocal microscopy . Image analyses and computational algorithms are then employed to extract measures of cell migration speed and intracellular stiffness via particle -tracking microrheology techniques . Major results show that ECM stiffness elicits an intracellular mechanical response only within the framework of physiologically relevant matrix environments and that a key cell -matrix attachment protein (the integrin ) plays an essential role in this phenomenon . Additional results indicate that a well -known breast cancer -associated biomarker (ErbB2 ) is responsible for sensitizing mammary cells to ECM stiffness . Finally , results also show that a switch in ECM architecture significantly hinders the migratory capacity of ErbB2 -associated cells , which may explain why the ErbB2 biomarker is detected with much higher frequency in early stage breast cancer than in later stage invasive and metastatic cancers . In total , these findings inform the fields of mechanobiology and cancer biology by systematically linking cell rheology , cell motility , matrix mechanics , and disease progression in cancer . |