Project title

Systems biology of responses of human cells to stress. Generation of heterogeneity, paracrine regulation and evolutionary analysis.

Research objectives

The aim of this proposal is to initiate new research on theory, experiment and evolutionary analysis of heterogeneity of human cells under stress, with emphasis on cancer. We will use multiscale systems biology approach, both computational and experimental.

Human cells in the organism and in culture exhibit substantial heterogeneity in morphology, kinetics and responses to stimuli. Heterogeneity adds robustness to the strategies adopted by cells. Robust strategies are important for normal cells, for example if they are attacked by pathogens, and for malignant cells if they are to evade agents such as chemotherapy and radiation. Indeed, the heterogeneity of human cancers constitutes the major obstacle against treatments. We aim to understand mechanisms of heterogeneity in normal and cancer cells, including cell communication involved in carcinogenesis. New stochastic and spatial models will be developed, describing:

In addition, analysis of regulatory sequences of genes involved in innate immune system response to carcinogens will be performed. Models will be validated using experiments designed in the project and existing data.

Understanding the heterogeneous response of biological cells to stress is critical to progress in biological and medical sciences. Particularly in cancer the range of behaviors of deregulated cells is immense. Channeling this heterogeneity will also contribute to synthetic biology, a new branch of engineering.

Research method

The methods to be used have to be multiscale (molecules to cells to tissues), a typical paradigm of systems biology. Detailed formulation of the Aims follows:

Impact of results

Intellectual impact of this research is that a comprehensive model of heterogeneity, including insights into evolution of genome deregulation in cancer, will contribute to understanding of dynamics growth and division regulation in normal cell and the stochastic and spatial aspects of dynamics of cancer initiation. The outcome is likely to influence thinking about interaction of stochastic and spatial effects. Single cell experiments will provide direct evidence concerning heterogeneity. Sequence control analysis will elucidate the evolutionary aspect of heterogeneity. Societal impact is based on the fact that understanding heterogeneity of paracrine regulation in cancer and signaling pathways activated in carcinogenesis is among the first steps toward developing effective biomarkers leading to early detection and treatments of cancer.

Pioneer research

Project includes pioneer research, which is highly interdisciplinary; it involves systems biology, engineering, and mathematical and computational approaches, as well as biological experimentation. Pioneer nature of Aim 1 stems from the fact that a stochastic theory of controls of cell proliferation and division, consistent with findings at the molecular level, is missing. Such theory existed 2 or 3 decades ago, but it has been outpaced by progress in biology. Aim 2 is pioneering because a quantitative stochastic model of carcinogenesis uniting genomic hits with heredity, selection and spatial communication does not exist while it is very much needed. Models which exist are incomplete in that they do not cover all aspects. As we demonstrate, stochasticity and spatial effects do not interact in a straightforward way, a fact which is universally underappreciated. Aim 3 is pioneering, since it is placing the heterogeneity controls of early carcinogenesis in an evolutionary perspective and helps elucidating genomic controls of carcinogenesis. At the same time, it involves verification of bioinformatics predictions by experiments.

More details

For more details see here.