Metastasis and therapy resistance cause over 90% of cancer-related deaths. Despite extensive ongoing efforts, no unique genetic or mutational signature has emerged for metastasis. Instead, the ability of genetically identical cells to adapt reversibly by exhibiting multiple phenotypes (phenotypic/non-genetic heterogeneity) and switch among them (phenotypic plasticity) is proposed as a hallmark of metastasis. Also, drug resistance can emerge from such non-genetic adaptive cellular changes. However, the origins of such non-genetic heterogeneity in most cancers are poorly understood. I will present our findings on a) how non-genetic heterogeneity emerges in a population of cancer, and b) what design principles underlie regulatory networks enabling non-genetic heterogeneity across multiple cancers. Our results unravel how systems-levels approaches integrating mechanistic mathematical modeling with in vitro and in vivo data can identify causes and consequences of such non-genetic heterogeneity.
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