If normal somatic cells can generate distinct, stable cell phenotypes, such as quiescent stem cells, proliferating progenitors and the large variety of differentiated cell types without altering the genome, then why is the acquisition of one malignant trait by progressing tumors, such as drug-resistance, stem cell-like self-renewal, invasion, etc., usually explained by genetic mutations? Tumor cell populations are highly heterogeneous which reflects to some extent normal tissue organization into compartments of stem cells and more differentiated cells. Thus, tumors may use the same non-genetic (""""""""epi-genetic"""""""") regulatory mechanisms to generate a variety of stable phenotypes as do normal tissues. Gene regulatory networks ol metazoan in fact appear to be wired so as to produce either a gradual stochastic dispersion of a trait (expression level of a gene) across a cell population or the distinct, stable variants of gene expression patterns (attractor states) - as epitomized by the various discrete cell types. Therefore, it is here hypothesized that this epigenetic cell population heterogeneity may produce phenotypic variants persistent enough to be selected for and hence, contribute to the classical (mutation-based) evolution of cells in tumor progression. Specifically, the rapid, population-wide appearance and disappearance of multi-drug-resistance in entire cell cultures support the idea of epigenetic adaptation. Moreover, expression of MDR1 that confers drug resistance is not an isolated idiosyncratic trait but an intrinsic property of adult stem cells, suggesting that tumors may in fact epigenetically switch between entire stable cellular programs that can be subjected to selection. To begin to address this new paradigm of epigenetic dynamics in tumor evolution, the Specific Aim 1 of this proposal will be to quantitate the dynamics of population dispersion in the expression of the multi-drug resistance gene, MDR1, in HL60 cells and the stability of epigenetic variants.
Specific Aim 2 is to create a """"""""genetic random-number generator"""""""" based on random recombination that can be externally initialized and is readable in single cells. It will be used in Specific Aim 3 to determine whether acquisition of drug resistance in vitro is mediated by clonal expansion of a random mutant or by a stochastic transitions between epigenetic states independently in multiple cells. In addition, gene expression profiling in this last Aim will reveal whether acquisition of drug resistance is linked to adoption of a stem cell phenotype, as would be expected if this process mirrors normal epigenetic switching between """"""""preprogrammed"""""""" cellular behaviors, since stem cells normally express MDR1. A better, quantitative knowledge of the neglected phenomenon of dynamic epigenetic heterogeneity not only will open a new perspective to metazoan cell regulation and cancer, but also could help optimize scheduling of chemotherapy so as to suppress selection of resistance and better target tumor stem cells. ? ? ? ? ? ? ?
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