Révéler les états des cellules souches, leurs transitions et leurs réseaux de régulation

 

Mohan Malleshaiah

Institut de recherches cliniques de Montréal [IRCM]

 

Domaine : cancer

Programme Chercheurs-boursiers - Junior 1

Concours 2018-2019

Cell fate choice is central to development and disease states such as cancer. Stem cells also have huge potential for regenerative and therapeutic medicine. It is however crucial to understand the mechanisms that underpin stem cell states to realize their potentials. Especially since they exhibit both molecular and functional heterogeneity. Cell fate specification is often thought to involve extremely complex networks. In contrast, my recent discovery implies major roles for simple networks in regulating cell fate choice. I found that while the pluripotency of stem cells is maintained by the recurring positive feedbacks among transcription factors – Nac1, Oct4, Sox2, Tcf3 and Nanog, their differentiation to distinct fates was promoted by reconfiguration of these same factors into newer networks. Measuring multiple proteins simultaneously in single pluripotent stem cells allowed me to identify distinct cell states and reprogram them to be totipotent.

These results have further led me to investigate: the molecular nature of distinct cell states and their transitions; understand the cell state specific gene regulatory transcription factor complexes; and study the mechanisms for tumor origins in the rare disease Wermer's syndrome. To address these, I will use integrated systems biology approaches by combining genomic and transcriptome analysis, single-cell experiments to simultaneously quantify multiple proteins, computational analysis and mathematical modelling. The results will lead to identification and characterization of key set of proteins and their networks, the modifications of which will enable us better control over cell fate transitions. For instance, to efficiently differentiate stem cells to a specific cell type for regeneration and to prevent cells from (re)establishing tumors.