Dynamical Systems Approach to decode cellular plasticity during cancer metastasis

Faculty: Mohit Kumar Jolly (BSSE) Annapoorni Rangarajan (MRDG)

Cancer metastasis – the spread of cancer cells from one organ to another – is responsible for 90% of deaths from solid tumors. It is a highly challenging process for cells with extremely high attrition rates (>98%), because metastasizing cells face a constantly changing and harsh environment during the entire process, and only the ones that can dynamically adapt to these changes by reversibly altering their multiple cellular traits can finally metastasize successfully. However, a dynamical understanding of how cells switch between different phenotypes and coordinate various traits (migration, drug resistance, metabolism etc.) remains incomplete.

This project focuses on decoding the underlying principles of cellular plasticity during metastasis using a dynamical systems biology approach that involves:

1.   Identifying complex regulatory networks enabling various facets of cellular plasticity, based on published literature
2.   Formulating mechanistic mathematical models to characterize the emergent nonlinear dynamics of these networks
3.   Simulating these networks (a set of coupled ODEs), correlating their simulation results with experimental and/or clinicopathological data, and generating specific experimental predictions to be tested

The project specifically focuses on epithelial-mesenchymal plasticity and plasticity between cancer stem cell (CSC) and a non-cancer stem cell state, and the student is expected to show a basic understanding of ordinary differential equations (ODEs) and nonlinear dynamics, and should be keen to pursue research in this interdisciplinary area of cancer systems biology (i.e. willing to read literature in both systems biology and cancer biology).

Relevant references:

1. Kolch, W.; Halasz, M.; Granovskaya, M.; Kholodenko, B. N. The dynamic control of signal transduction networks in cancer cells. Nat. Rev. Cancer  2015, 15 (9), 515–27. doi: 10.1038/nrc3983
2. Jolly, M. K., Boareto, M.; Huang, B.; Jia, D.; Lu, M.; Ben-Jacob, E.; Onuchic, J.N.; Levine, H. Implications of the hybrid epithelial/mesenchymal phenotype in metastasis. Front. Oncol. 2015, 5, 155. doi: 10.3389/fonc.2015.00155

3. Magi, S.; Iwamoto, K.;  Okada-Hatakeyama, M. Current status of mathematical modeling of cancer – From the viewpoint of cancer hallmarks. Curr. Opin. Syst. Biol. 2017, 2, 38-47. doi: 10.1016/j.coisb.2017.02.008