MAE-A Room 303
939 Sweetwater Dr
Gainesville, FL 32611
Out of Touch: Depletion of Mechanosensors Drives
Wound-Healing and Cancer
Michael Sheetz, Ph.D., Director,
Mechanobiology Institute of Singapore
National University of Singapore and
Biochemistry and Molecular Biology
University of Texas Medical Branch, Galveston, TX
Since repeated tissue damage correlates with increased risk of cancer, there could be a correlation between tissue regeneration and cancer in that both involve growth in adult tissues. Indeed microRNA-21 levels are upregulated in both tissue regeneration and cancer. miRNA-21 causes depletion of several proteins but particularly, tropomyosin (Tpm) 2.1 depletion blocks rigidity sensing and causes growth on soft surfaces. In over forty cancer cell lines tested, at least 75% were missing major components of the rigidity sensing complex (about 60% had low Tpm 2.1). The rigidity sensing complex (about 2 m in length) contracts matrix adhesions by ~100nm; and if the force generated is greater than ~25 pN, then adhesions are reinforced, and cells can grow (Wolfenson et al., 2016. Nat Cell Bio. 18:33). However, if the surface is soft and matrix force low, then the rigidity sensor in normal cells causes apoptosis by DAPK1 activation (Qin et al., 2018 BioRxiv. 320739). Transformed cancer cells lack rigidity-sensing contractions and grow on soft surfaces. Restoration of rigidity sensing in cancer cells by normalizing cytoskeletal protein levels (most often by restoring Tpm 2.1 levels) restores rigidity-dependent growth (Yang, B. et al., 2018 Nature Mat. In Press). Surprisingly, we find that cyclic mechanical stretch of transformed cancer cells activates apoptosis through calpain-dependent apoptosis. Restoring rigidity sensing in transformed cancer cells blocked stretch-induced apoptosis and caused rigidity-dependent growth (Tijore et al., 2018 BioRxiv. 491746). Conversely, normal cells become stretch-sensitive for apoptosis after transformation by depleting rigidity sensors through Tpm2.1 kockdown or knockdown of other tumor suppressor proteins needed for rigidity sensing. Thus, it seems that stretch sensitivity is a weakness of many cancer cell lines and this is related to the transformed cell state and not to the tissue type or other factors. Depletion of the rigidity sensor to allow regenerative growth is found in the great majority of cancer cells and results in transformed growth. Tumor growth involves many different aspects such as telomere elongation or changes in metabolism, but transformation appears necessary.
Dr. Michael Sheetz recently moved to Biochemistry and Molecular Biology Department at Univ. of Texas Medical Branch where he will head a Mechanomedicine Program. He was the Founding Director of the Mechanobiology Institute at National University of Singapore and his recent work has defined the molecular mechanisms of rigidity sensing and matrix control of cell growth. In 2012, he was the recipient of the Lasker and Wiley Prizes for Biomedical Sciences for work done on in vitro motility assays and the discovery of kinesin. He has had an appointment at Columbia University since 2000 and prior to that he was Chair of Cell Biology at Duke University Medical Center (1990-2000).