Assistant Professor, Rice University
B.A., University of Pennsylvania, 2003
Ph.D., University of Chicago, 2008
Self-organized developmental patterning and modeling the cancer microenvironment
Research in the laboratory utilizes a combination of quantitative experiments and mathematical modeling to study signaling dynamics and spatial cellular organization in both normal development and during cancer progression. Research focuses on three major related areas:
Self-organized developmental patterning. During development, the cells of the embryo create patterns of cell fates and gene expression. We recently showed that some of the earliest steps of the patterning can be recapitulated in vitro with human embryonic stem cells using micropatterning technologies. This system allows us to study development using a “bottom-up” approach, in which we attempt to recapitulate and manipulate the development of hESCs. We are now using this system to address a number of questions regarding early development. What are the physical mechanism by which extracellular signals spread and how do cells use these signals to self-organize into fate patterns? What is the relationship between the dynamics of signaling in an individual cell and the fate it ultimately adopts? These questions are difficult to address in intact embryos, particularly in mammalian embryos that develop in utero, however, the hESC system allows us to finely manipulate both physical and chemical variables and to directly observe a variety of signaling and fate reporters in individual cells. The wealth of data generated from these experiments is organized and extended using a mathematical modeling approach that determines the landscape of fates available to a cell during early development and the relationship between those fates.
Modeling the cancer microenvironment. Interactions between healthy and diseased cells play an important role in cancer progression, however, little is known about how the parameters of those interactions shape the response. Using micropatterning technologies, we will recreate the geometry of the tumor microenvironment for ovarian cancer and study how the relative position of different cell types impacts outcomes such as cell proliferation and migration. We will also utilize signaling reporters to the TGF-β and Wnt pathways (known to be important for the interaction between ovarian cancer cells and cancer associated fibroblasts) to understand the dynamics of how these cells communicate. Ultimately, we hope that by understand the interactions between these different types of cells, we will be able to engineer particular dynamic signaling perturbations that can disrupt support for the cancer cells without affecting interactions between the healthy cells.
Laslo P, Spooner CJ, Warmflash A, Lancki DW, Lee HJ, Sciammas R, Gantner BN, Dinner AR, Singh H (2006) Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell 126:755-766.
Warmflash A, Dinner AR (2008) Signatures of combinatorial regulation in intrinsic biological noise. Proceedings of the National Academy of Sciences USA 105:17262-17267.
Warmflash A, Bhimalapuram P, Dinner AR (2007) Umbrella sampling for nonequilibrium processes. Journal of Chemical Physics 127:154112.
Sciammas R, Li Y, Warmflash A, Song Y, Dinner AR, Singh H (2011) An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling. Molecular Systems Biology 7:495.
Warmflash A, Zhang Q, Sorre B, Vonica A, Siggia ED, Brivanlou AH (2012) Dynamics of TGF-β signaling reveal adaptive and pulsatile behaviors reflected in the nuclear localization of transcription factor Smad4. Proceedings of the National Academy of Sciences USA 109:E1947-E1956.
Warmflash A, Arduini BL, Brivanlou AH (2012) The molecular circuitry underlying pluripotency in embryonic stem cells. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 4:443-456.
Warmflash A, Francois P, Siggia ED (2012) Pareto evolution of gene networks: an algorithm to optimize multiple fitness objectives. Physical Biology 9:056001.
Warmflash A, Sorre B, Etoc F, Siggia ED, Brivanlou AH (2014) A method to recapitulate early embryonic spatial patterning in human embryonic stem cells.
Nature Methods 11:847-854.
Sorre B, Warmflash A, Brivanlou AH, Siggia ED (2014) Encoding of temporal signals by the TGF-β pathway and implications for embryonic patterning. Developmental Cell 30:334-342.
Aryeh Warmflash, Ph.D.
Department of BioSciences
344 Anderson Biological Labs
Houston, Texas 77030, U.S.A.
Tel: (713) 348-2456