We seek to establish the mechanobiological basis of malignant transformation. Findings from my laboratory indicate that a critical feature of cancer cells, and in fact what determines their ability to grow in abnormal conditions (e.g., soft agar), is their inability to measure the rigidity of the matrix around them. We have discovered a rigidity sensing module that is similar to a sarcomere and contains many cytoskeletal components as well as receptor tyrosine kinases (RTKs). When individual components of this module are depleted in cells, it cannot form and the cells will grow on soft surfaces. Specifically, depletion of the cytoskeletal tumor suppressors, tropomyosin 2.1 (Tpm2.1), myosin I...

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We seek to establish the mechanobiological basis of malignant transformation. Findings from my laboratory indicate that a critical feature of cancer cells, and in fact what determines their ability to grow in abnormal conditions (e.g., soft agar), is their inability to measure the rigidity of the matrix around them. We have discovered a rigidity sensing module that is similar to a sarcomere and contains many cytoskeletal components as well as receptor tyrosine kinases (RTKs). When individual components of this module are depleted in cells, it cannot form and the cells will grow on soft surfaces.

Specifically, depletion of the cytoskeletal tumor suppressors, tropomyosin 2.1 (Tpm2.1), myosin IIA and alpha-actinin4 all cause the loss of rigidity sensing modules and growth on soft agar. Further, we find that many RTKs, including known tumor drivers EGFR and HER2, are involved in control of the modules, and remarkably act without ligands. In normal cells, when the rigidity sensing modules are present, cells activate apoptosis through the action of a kinase that phosphorylates Tpm2.1. Interestingly, many cancers have elevated levels of the microRNA, miR-21, which reduces levels of Tpm2.1.

Our objectives are: 1) To determine how the loss of rigidity sensing modules causes a change in cytoplasmic organization to enable transformed growth. 2) To discover how normal rigidity-sensing modules activate apoptosis on soft surfaces, and 3) To identify therapeutic targets among mechanosensing components. Our long-term goals are to develop methods to specifically inhibit changes in cytoplasmic organization that support transformed growth and restore apoptotic pathways in the absence of rigidity sensing modules because that would specifically target many cancer cells.

Further, we believe that there are other mechanosensory mechanisms that are altered in cancer and that our methods can uncover those pathways with the possibility of developing treatments to target them specifically.

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