Harnessing optogenetics to diagnose and therapeutically rewire cancer cell signaling In recent years, advances in microscopy, sequencing, and proteomics have had a dramatic impact on our ability to probe the inner workings of cells and tissues. These tools have revealed that cells are remarkably complex information processing devices: external inputs activate many intracellular networks with complex dynamics. Yet despite the progress in measuring the cell's outputs, we have lacked analogous control over the inputs we can deliver to probe and perturb these complex networks. By replacing chemical stimuli with light, optogenetic tools can be used to apply and remove inputs with high spatial and temporal precision. Here, I propose to bring this precise input control to bear on two long-standing problems in cancer biology, a field where it has so far had limited impact. First, I will develop an approach termed ?optogenetic profiling?, which aims to directly measure how growth signaling is altered in tumor cells by measuring cellular responses to a rich set of input stimuli. Rooted in engineering, this approach is akin to probing an electronic circuit with a different signals to characterize its function, and can be highly informative even when the exact wiring diagram is unknown. This approach may offer a key to interpreting genomic data, allowing us to group cell lines with different mutations into shared functional classes. It could also have a large impact on treatment: identifying which pathway is deregulated may immediately suggest which targeted pathway inhibitors will be effective. Second, I will explore how light-induced protein aggregation can be used to therapeutically rewire cancer cell signaling. Tumor cells rely on signaling changes that both amplify proliferation and suppress apoptosis, but current therapies are typically limited to inhibiting pro-growth signaling. Here, I will test whether light-induced co-clustering of signaling proteins can perform two other therapeutic functions: amplifying apoptotic signaling or diverting growth inputs to cell-death outputs. The studies proposed will not only uncover fundamental principles in cell signaling but could usher in new approaches for cancer diagnosis (by functionally profiling signaling pathway responses) and treatment (by engineering gain-of-fuction therapies based on signaling enzyme clustering).
Relevancy Cancer is driven by complex sets of mutations that drive cell growth and suppress cell death. Here, I propose to use tools from the emerging field of optogenetics to uncover how these complex processes are altered in cancer cells and manipulate them for therapeutic benefit. This work could provide a new approach to diagnose cancer based on the functional changes that drive growth in each tumor, and to therapeutically ?rewire? cancer cells to selectively kill them.
| Zhao, Evan M; Zhang, Yanfei; Mehl, Justin et al. (2018) Optogenetic regulation of engineered cellular metabolism for microbial chemical production. Nature 555:683-687 |
| Bugaj, L J; Sabnis, A J; Mitchell, A et al. (2018) Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras-Erk pathway. Science 361: |
| Barrio-Real, Laura; Lopez-Haber, Cynthia; Casado-Medrano, Victoria et al. (2018) P-Rex1 is dispensable for Erk activation and mitogenesis in breast cancer. Oncotarget 9:28612-28624 |
| Dine, Elliot; Toettcher, Jared E (2018) Optogenetic Reconstitution for Determining the Form and Function of Membraneless Organelles. Biochemistry 57:2432-2436 |
| Tanner, Lukas Bahati; Goglia, Alexander G; Wei, Monica H et al. (2018) Four Key Steps Control Glycolytic Flux in Mammalian Cells. Cell Syst 7:49-62.e8 |
| Dine, Elliot; Gil, Agnieszka A; Uribe, Giselle et al. (2018) Protein Phase Separation Provides Long-Term Memory of Transient Spatial Stimuli. Cell Syst 6:655-663.e5 |
| Johnson, Heath E; Toettcher, Jared E (2018) Illuminating developmental biology with cellular optogenetics. Curr Opin Biotechnol 52:42-48 |
| Goglia, Alexander G; Wilson, Maxwell Z; DiGiorno, Daniel B et al. (2017) Optogenetic Control of Ras/Erk Signaling Using the Phy-PIF System. Methods Mol Biol 1636:3-20 |
| Johnson, Heath E; Goyal, Yogesh; Pannucci, Nicole L et al. (2017) The Spatiotemporal Limits of Developmental Erk Signaling. Dev Cell 40:185-192 |
| Shin, Yongdae; Berry, Joel; Pannucci, Nicole et al. (2017) Spatiotemporal Control of Intracellular Phase Transitions Using Light-Activated optoDroplets. Cell 168:159-171.e14 |
Showing the most recent 10 out of 11 publications
