Research Groups

Part 1: Continuing Suzanne Eaton’s mission

Discover how tissue patterning systems influence growth and morphogenesis during development and disease

The relationship between tissue patterning and growth has been obvious since 1924, when Hans Spemann and Hilde Mangold generated a second body axis by transplanting the blastopore lip of one newt embryo to another. This piece of organizing tissue (which, as we now know, produces powerful signaling molecules called morphogens) instructs the surrounding tissue, not only to differentiate new head structures, but also to grow by precisely the correct amount to accommodate them. In the almost 100 years that have followed, we have identified and studied these morphogens and others like them. We have a working understanding of the cellular machinery that transduces their signals and how they spread through tissue. We have outlined the basic principles by which morphogen gradients control gene expression to produce spatial patterns of tissue differentiation. But the coupling of patterning to growth is still a mystery. How are these two functions– growth and patterning – are logically linked together? How does morphogen signaling regulate the amount and orientation of tissue growth? What ensures that growth stops at precisely the size sufficient to produce the pattern of structures that must be built?

To control the amount and orientation of tissue growth, morphogen signaling must eventually act on the basic metabolic and mechanical properties of constituent cells. Furthermore, they must be communicating with other parts of the body via hormonal signaling, in order for the entire organism to develop in synchrony and with the right proportions. Our goal is to elucidate the connections between morphogen signaling, hormonal signaling, cell metabolism, and cell mechanics to understand how their interactions combine to regulate tissue growth.

Part 2: Beginning Natalie Dye’s mission

Elucidate the mechanisms regulating tissue morphology and harness this knowledge for the management of human cancers of epithelial origin.

Over the last century, significant technical and conceptual advances in the field of genetics and molecular biology have provided valuable insight into the genetic requirements for biological processes. Nonetheless, it is still difficult to explain how changes at the molecular level lead to different outcomes in development and disease. In developmental biology, for example, we have identified numerous molecules that are required for patterning and tissue growth, including the morphogens described above. But how do these molecules come together to create a 3D tissue with a precise size and shape that is necessary for its function? Likewise, in medicine, it is become feasible to sequence individual patients to identify molecular signatures at the DNA and RNA level. Yet it has proven difficult to interpret how these molecular differences lead to certain disease outcomes, such as whether or not a tumor will metastasize. Thus, there is a general challenge that exists throughout the life sciences – how can we relate specific molecular changes to complex consequences at larger scales? Answering this question is essential, both for understanding the fundamental question of how organisms look the way they do and for designing effective, individualized treatment strategies for human disease.

Our approach to bridging this gap in scales is to characterize systems at the intermediate, meso-scale and uncover the physical principles that organize collective cell behavior. To gain insight into fundamental mechanisms that transform epithelial sheets into complex tissue morphologies during development, we are using the genetically tractable model organism Drosophila, as well as human induced pluripotent stem cell cultures. In the near future, we will be applying our techniques and concepts to human epithelial cancers, studying the morphology and dynamics of patient-derived tumor organoids to gain new insight into individual variability in human cancer progression.