Institute for Systems Biology

About: Institute for Systems Biology is a nonprofit organization based out in Seattle, Washington, United States. It is known for research contribution in the topics: Population & Proteomics. The organization has 1277 authors who have published 2777 publications receiving 353165 citations.

Dizzy: stochastic simulation of large-scale genetic regulatory networks

Abstract: We describe Dizzy, a software tool for stochastically and deterministically modeling the spatially homogeneous kinetics of integrated large-scale genetic, metabolic, and signaling networks. Notable features include a modular simulation framework, reusable modeling elements, complex kinetic rate laws, multi-step reaction processes, steady-state noise estimation, and spatial compartmentalization.

Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse: 'What does not kill me strengthens me'.

Abstract: Therapy resistance and tumour relapse after drug therapy are commonly explained by Darwinian selection of pre-existing drug-resistant, often stem-like cancer cells resulting from random mutations. However, the ubiquitous non-genetic heterogeneity and plasticity of tumour cell phenotype raises the question: are mutations really necessary and sufficient to promote cell phenotype changes during tumour progression? Cancer therapy inevitably spares some cancer cells, even in the absence of resistant mutants. Accumulating observations suggest that the non-killed, residual tumour cells actively acquire a new phenotype simply by exploiting their developmental potential. These surviving cells are stressed by the cytotoxic treatment, and owing to phenotype plasticity, exhibit a variety of responses. Some are pushed into nearby, latent attractor states of the gene regulatory network which resemble evolutionary ancient or early developmental gene expression programs that confer stemness and resilience. By entering such stem-like, stress-response states, the surviving cells strengthen their capacity to cope with future noxious agents. Considering non-genetic cell state dynamics and the relative ease with which surviving but stressed cells can be tipped into latent attractors provides a foundation for exploring new therapeutic approaches that seek not only to kill cancer cells but also to avoid promoting resistance and relapse that are inherently linked to the attempts to kill them.

Non-Darwinian dynamics in therapy-induced cancer drug resistance

Abstract: The development of drug resistance, the prime cause of failure in cancer therapy, is commonly explained by the selection of resistant mutant cancer cells. However, dynamic non-genetic heterogeneity of clonal cell populations continuously produces metastable phenotypic variants (persisters), some of which represent stem-like states that confer resistance. Even without genetic mutations, Darwinian selection can expand these resistant variants, which would explain the invariably rapid emergence of stem-like resistant cells. Here, by using quantitative measurements and modelling, we show that appearance of multidrug resistance in HL60 leukemic cells following treatment with vincristine is not explained by Darwinian selection but by Lamarckian induction. Single-cell longitudinal monitoring confirms the induction of multidrug resistance in individual cells. Associated transcriptome changes indicate a lasting stress response consistent with a drug-induced switch between high-dimensional cancer attractors. Resistance induction correlates with Wnt pathway upregulation and is suppressed by β-catenin knockdown, revealing a new opportunity for early therapeutic intervention against the development of drug resistance.