36th Annual Alexander Graham Christie Lecture

February 21, 2019 @ 3:00 pm – 4:00 pm
26 Mudd Hall, Homewood Campus
3400 N Charles St
Baltimore MD 21218
Department of Mechanical Engineering

The 36th Annual Alexander Graham Christie Lecture

*Reception to be held directly afterwards, lobby area of Mudd Hall


“Mechanosensing Depletion Drives Regeneration and Cancer”

Presented by Professor Michael Sheetz, Ph.D., Director

Mechanobiology Institute of Singapore, National University of Singapore and

Department of Biological Sciences, Columbia University

Since repeated tissue damage correlates with increased risk of cancer, there could be a correlation between tissue regeneration and cancer in that they 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 BioRxiv. 221176). 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 mechanosensor to allow regenerative growth can lead to sustained loss of mechanosensing that enables cancerous growth.

Professor Michael Sheetz is a cell biologist at Columbia University and a Distinguished Professor and the founding Director of the Mechanobiology Institute at the National University of Singapore. He pioneered mechanobiology and biomechanics. In 1968, Sheetz earned a bachelor’s degree at Albion College, and in 1972 received his Ph.D. at the California Institute of Technology. In 1985 he became a professor of cell biology and physiology at the Washington University in St. Louis, Missouri. Since 1990 he is the William R. Kenan, Jr. Professor of Cell Biology at Columbia University, New York. He has also been a professor at Duke University.

Back to top