Interdisciplinary Physics Seminar -- SATE
November 20th , FRIDAY 11:30 a.m. , 1400 BPS
Sui Huang, Institute for Systems Biology Seattle
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CRITICAL STATE TRANSITIONS, REBELLIOUS CELLS and WHY IT IS SO HARD TO ERADICATE CANCER CELLS
Sui Huang, MD, PhD.
Cancer cells' ability to occupy a vast diversity of biologically distinct, inheritable cell states without genetic mutations, but by harnessing the same phenotypic plasticity that drives development and regeneration adds a layer of complexity to the standard model of Darwinian somatic selection of mutants. If we escape the orthodoxy of a rigid 1:1 mapping between genotype and phenotype that human mind is heir to and that underlies the theory of somatic evolution of cancer, then the need to invoke genetic mutations as the sole driver of tumor progression is moot.
In this talk I will present the theoretical framework and experimental findings supporting this (no so new) thinking. We have formalized non-genetic cell phenotype plasticity as a dynamical system governed by the gene regulatory network. In this framework the distinct, stable biological cell states are attractor states in the high-dimensional gene expression state space. Herein, cancer cells occupy particular (normally forbidden) attractor states, and therapy constitutes a perturbation that seeks to push cells out of these cancer attractors into those that represent the differentiated, quiescent or apoptotic cell fates.
In this formalism a transition between stable attractor state is a symmetry-breaking bifurcation in which the current attractor is destabilized and other attractors become accessible. This constitutes a critical state transition in a high-dimensional space. Importantly, in a complex multi-stable system ("rugged epigenetic landscape") this process of destabilization also opens up new access to "hidden" attractor states never intended to be occupied by a cell and even more different from the physiological ones. Now, as the cancer cells exit the cancer attractor during treatment-induced destabilization of their state, many will indeed, as desired, move to the target phenotype (the apoptotic state) - but some may also "spill" into the newly accessible nearby hidden attractors which may represent even more stem-like cells, hence more malignant states. These aberrant non-killed "rebellious cells" triggered by sub-lethal therapy stress may present the seed for recurrence.
It is in this sense that recurrence and resistance of tumors after treatment is not so much described by Darwinian "survival of the fittest " but perhaps more aptly by Nietzsche's principle: "What does not kill me strengthens me". Because of the ubiquity of non-genetic plasticity and the fundamental nature of phenotypic destabilization, it is likely that the latter principle widely applies. It does of course not exclude Darwinian selection of genetic mutants -in contrary it facilitates it by enhancing the probability of a cell surviving treatment and by pushing these non-killed cells in the direction of a more malignant phenotype.
Indeed, we observed in single-cell resolution measurements of cells responding to treatment or undergoing physiological phenotype transitions, the signatures of postulated critical state transition. Experiments also exposes the rebellious cells predicted by theory: cells that move into attractors in opposite direction from that of the desired transition. It follows the general postulate that there is an inherent limitation to any, however selectively targeting cancer drug, as long as it seeks to destabilize the cancerous state. But this opens a new window for therapeutic intervention that goes beyond simply "more efficient killing": we need to prevent therapy-induced "strengthening" of the non-killed cancer cells.
