Study of the Regulative Role of Integrin Tension in the Formation and Function of Plasma Membrane Protrusions in Cancer Cells

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Metastasis, which is invasion of normal tissues by cancer cells, is the main cause of cancer patient death. The cells that metastasize have special sites on their surfaces call "invadopodia" that make it possible for the cells to spread. Multiple lines of indirect evidence suggest that invadopodia are use mechanical loads are part of their invasion function. How these forces function in invasion, however, remains unknown. Two molecular tension tools were developed by the investigators and will be used to measure loading of the invadopodium. This research will determine how tension affects invadopodia formation and facilitates cell motion. High resolution cellular force maps will also be created as a biomechanical assay for the detection of cancer cells in pre-clinical models. Overall, this research will yield valuable insights to the mechanobiology of invadopodia, and potentially create a new tool for assessing biomechanically the probability that cancer cells will invade. As part of the research project, the investigators will provide summer research opportunities to undergraduate students recruited through the NSF LSAMP IINSPIRE program which recruits underrepresented undergraduate students to labs for summer research. Also a one-day workshop featuring aspects of the research imaging progress will be created for 60 undergraduates in the PI's university department at Iowa State.The invadopodium is a protein complex formed in cancer cell membranes which is and involved in matrix degradation and cancer metastasis. Mechano-sensitive protein integrins are expected to transmit force to critically regulate the formation and function of invadopodia. However, such force has not been studied in invadopodia due to previous technical barriers. The goal of this project is to characterize integrin-transmitted molecular tension (integrin tension) and investigate its fundamental role in the formation and function of invadopodia. Using innovative molecular tension tools developed by the PI, the research in this project will first calibrate and image integrin tension in invadopodia with high resolution and sensitivity. Integrin tension and various structural proteins will be co-imaged at 0.3 micron resolution to reveal the force-structure interplay in invadopodia. Next, integrin tension will be globally and quantitatively knocked down to a designed level using a tension modulator, the consequent structural deficiency and function loss of invadopodia in matrix degradation will be examined to determine the role of integrin tension in the activities of invadopodia. At last, high-resolution tension map contributed by integrins in both invadopodia and focal adhesions will be tested as a biomarker for the identification of cancer cells from a large population of regular cells. This unique biomechanical assay has the potential to provide a fast and convenient approach for the detection of circulating tumor cells in patient blood samples.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.