Alladi Ramakrishnan Hall

Systems biology of cellular transitions during cancer metastasis: can theory help understand cancer biology?

Mohit Kumar Jolly

Center for Theoretical Biological Physics, Rice University

Metastasis – the spread of cancer to distant organs through blood circulation – causes more than 90% of all cancer-related deaths. To leave the home organ and enter the bloodstream, tumor cells lose their cell-cell adhesion and gain the ability to migrate and invade – a process known as Epithelial-Mesenchymal Transition (EMT). Upon reaching distant organs, these cells stop migrating and regain cell-cell adhesion – a process called Mesenchymal-Epithelial Transition (MET) – to form new tumors. EMT and MET are largely considered as binary processes, and thus a hybrid epithelial/mesenchymal (E/M) cell state has been tacitly assumed as transient. My work suggests that a hybrid E/M state can be stably maintained by cells, and can be more aggressive than cells in purely epithelial or mesenchymal state. This talk will describe how mechanism-based mathematical modeling of regulatory networks underlying EMT or MET have driven these novel insights and generated exciting hypotheses that have been verified experimentally. Modeling these networks reveals tristability (co-existence of three cellular states – E, M and hybrid E/M) and identifies ‘phenotypic stability factors’ (PSFs) – a set of players that can stabilize a hybrid E/M state. Moreover, modeling EMT/MET networks together with those controlling tumor-initiation reveals that hybrid E/M cells are more likely to form metastases as compared to fully E or fully M ones. Further, modeling of EMT/MET networks coupled with specific cell-cell communication pathways illustrates how hybrid E/M cells can lead to form clusters of Circulating Tumor Cells (CTCs) – the primary ‘villains’ of metastasis. Finally, higher levels of one or more PSFs associate with poor patient outcome across many cancer types. Collectively, my work decodes the systems-level emergent dynamics of biochemical networks that regulate tumor progression, and uncovers many previously unknown accelerators of metastasis.