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Trogdon, M.

Publications and source records attributed to Trogdon, M..

2 recordsLinked to original sources

Coordinating cell polarization and morphogenesis through mechanical feedback

Many cellular processes require cell polarization to be maintained as the cell changes shape, grows or moves. Without feedback mechanisms relaying information about cell shape to the polarity molecular machinery, the coordination between cell polarization and morphogenesis, movement or growth would not be possible. Here we theoretically and computationally study the role of a genetically-encoded mechanical feedback (in the Cell Wall Integrity Pathway) as a potential coordination mechanism between cell morphogenesis and polarity during budding yeast mating projection growth. We developed a coarse-grained continuum description of the coupled dynamics of cell polarization and morphogenesis as well as 3D stochastic simulations of the molecular polarization machinery in the evolving cell shape. Both theoretical approaches show that in the absence of mechanical feedback (or in the presence of weak feedback), cell polarity cannot be maintained at the projection tip during growth, with the polarization cap wandering off the projection tip, arresting morphogenesis. In contrast, for mechanical feedback strengths above a threshold, cells can robustly maintain cell polarization at the tip and simultaneously sustain mating projection growth. These results indicate that the mechanical feedback encoded in the Cell Wall Integrity pathway can provide important positional information to the molecular machinery in the cell, thereby enabling the coordination of cell polarization and morphogenesis. Author summaryCell migration, morphogenesis and secretion are among the vast number of cellular processes that require cells to define a preferred spatial direction to perform essential tasks. This is achieved by setting an intracellular molecular gradient that polarizes the cell. While the molecular players involved in cell polarization and some of the mechanisms that cells use to establish such molecular gradients are known, it remains unclear how cells maintain polarization as they dramatically change shape during morphogenesis, migration, etc. Here we identify a potential feedback control mechanism, encoded genetically in cells, that provides the molecular polarization machinery with the necessary information about cell geometry to maintain cell polarization during cell shape changes.

biophysics

Inhibition of both mutant and wild-type RAS-GTP in KRAS G12C colorectal cancer through cotreatment with G12C and EGFR inhibitors

The combination of KRAS G12C inhibitors with EGFR inhibitors has reproducibly been shown to be beneficial. Here, we reveal a new benefit of this combination: it effectively inhibits both wild-type and mutant RAS. A role for WT RAS inhibition has not previously been reported for this important combination of targeted therapies. We believe that targeting both mutant and wild-type RAS helps explain why this combination of inhibitors is effective.

cancer biology