ICB Seminar

20.05.2019

Biochemical trajectories in developing tissues and cancer

Ph.D. Yogesh Goyal, Princeton University

Biological processes, such as tissue development and homeostasis, are complex yet precise and robust. At the same time, certain perturbations can disrupt this robustness and specificity, leading to abnormal outcomes, i.e. disease. I am broadly interested in understanding the origins of such abnormalities, which often result from alterations in the spatiotemporal dynamics of underlying biochemical signaling processes. 

In the first part of this talk, I will describe some of the quantitative frameworks we developed to monitor and control the effects of signaling perturbations in developing fly tissues. We used these tools to study the effect of pathogenic mutations on developmental outcomes. Studies in test tubes and cultured cells have shown that disease-causing mutations in the enzyme makes it constitutively active, leading to a higher than normal signaling output. Instead, using our highly resolved spatiotemporal experimental platforms, we found that these mutations can both increase and reduce the levels of signaling output in developing tissues, a surprising, yet significant result. Our discovery has implications for the basic understanding of a large class of developmental abnormalities and urges caution when it comes to considering their pharmacological treatments.

The second part of the talk will focus on cellular plasticity and reprogramming in the melanoma model of therapy resistance. In particular, recent studies have shown that rare subpopulations (1 in 3000) of melanoma cells exhibit non-genetic plasticity where they occupy a transient state capable of withstanding drug exposure and can be reprogrammed to become stably resistant upon drug addition. I will present our ongoing experimental and computational work on a) understanding the origins of these rare transient cellular states and b) mapping the lineage trajectories from transiently plastic states to drug-induced reprogrammed state(s) at single cell resolution. Together, our multiscale approaches can be used to elucidate and synthesize biochemical and phenotypic trajectories in response to perturbations.

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