Matrix rigidity regulates cancer cell growth by modulating cellular metabolism and protein synthesis.

TILGHMAN RW, BLAIS EM, COWAN CR, SHERMAN NE, GRIGERA PR, ET AL.

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2012 vol. 7 p. 1 - 11

1932-6203

AbstractBackground: Tumor cells in vivo encounter diverse types of microenvironments both at the site of the primary tumor and atsites of distant metastases. Understanding how the various mechanical properties of these microenvironments affect thebiology of tumor cells during disease progression is critical in identifying molecular targets for cancer therapy.Methodology/Principal Findings: This study uses flexible polyacrylamide gels as substrates for cell growth in conjunctionwith a novel proteomic approach to identify the properties of rigidity-dependent cancer cell lines that contribute to theirdifferential growth on soft and rigid substrates. Compared to cells growing on more rigid/stiff substrates (.10,000 Pa), cellson soft substrates (150–300 Pa) exhibited a longer cell cycle, due predominantly to an extension of the G1 phase of the cellcycle, and were metabolically less active, showing decreased levels of intracellular ATP and a marked reduction in proteinsynthesis. Using stable isotope labeling of amino acids in culture (SILAC) and mass spectrometry, we measured the rates ofprotein synthesis of over 1200 cellular proteins under growth conditions on soft and rigid/stiff substrates. We identifiedcellular proteins whose syntheses were either preferentially inhibited or preserved on soft matrices. The former categoryincluded proteins that regulate cytoskeletal structures (e.g., tubulins) and glycolysis (e.g., phosphofructokinase-1), whereasthe latter category included proteins that regulate key metabolic pathways required for survival, e.g., nicotinamidephosphoribosyltransferase, a regulator of the NAD salvage pathway.Conclusions/Significance: The cellular properties of rigidity-dependent cancer cells growing on soft matrices arereminiscent of the properties of dormant cancer cells, e.g., slow growth rate and reduced metabolism. We suggest that theuse of relatively soft gels as cell culture substrates would allow molecular pathways to be studied under conditions thatreflect the different mechanical environments encountered by cancer cells upon metastasis to distant sites.