In the Fritz B. Burns Cancer Research Laboratory, we integrate molecular/biochemical approaches and mass spectrometry to discover fundamental molecular mechanisms that control the growth and survival of cancer cells. A better understanding of these mechanisms gives us the tools to develop more effective and targeted cancer therapies.
A central project in our lab focuses on the protein 14-3-3, which interacts in a phosphorylation-dependent manner with a vast network of partners that regulate all aspects of cancer biology: cell cycle, anti-apoptotic signaling, Warburg metabolism, and motility/metastasis. In this way, 14-3-3 acts as a cellular hub that orchestrates an entire program of oncogenesis and cancer growth (Figure 1). We have approached 14-3-3 from various angles, including the direct therapeutic targeting of 14-3-3 in cancer and its use as a phospho-probe to guide us to dynamic and targetable cancer mechanisms. Currently, we have several projects that have sprung from our work on 14-3-3, many of which have now taken on a life of their own:
1) Mechanisms of autophagy.
Cancer cells respond to a variety of stresses by activating a pro-survival recycling process called autophagy (translated literally as ‘self-eating’). Our work in this area started with the discovery of a 14-3-3-mediated molecular switch that controls one of the chief activators of autophagy, a protein called ATG9A. Since then, our work has focused on a variety of mysteries about how ATG9A and its interacting partners are regulated to control different steps in the autophagy process.
2) Regulation of oncogenic tyrosine kinases.
In order for a normal cell to become cancerous, it must acquire constitutive growth signaling by activating one or a combination of oncogenic tyrosine kinases. Our work in this area has harnessed 14-3-3 as a guide to identify tyrosine kinase mechanisms that play central roles in cancer growth and motility. This work recently led to the identification of a novel cancer therapeutic that is currently under development.
3) Other emerging 14-3-3-mediated mechanisms of cancer growth.
An ongoing effort in our lab is aimed at elucidating the vast network of 14-3-3 interactions (the ‘spokes’ off the 14-3-3 hub in figure 1). From such data, we identify critical interactions (like those above) and seek to understand 1) how the interaction is regulated and linked to the larger signaling network of the cell; 2) how 14-3-3 binding affects the interacting partner (e.g., inhibition, activation, sequestration); and 3) how the interaction regulates critical features of cancer. This aspect of our work provides a wellspring of exciting research adventures into the leading edge of potentially targetable cancer mechanisms.
4) Targeting the hub itself.
This project is based on the rationale that targeting 14-3-3 itself, as opposed to specific 14-3-3 interactions, could provide the most robust anti-cancer benefit. Toward this end, we have used our understanding of the molecular basis of 14-3-3 interactions to collaborate in the design of small molecule inhibitors of 14-3-3. In addition, we have used mass spectrometry and bioinformatics to identify post-translational modifications on 14-3-3 that control its interactions with binding partners. This work reveals how targeting the enzymes that control lysine acetylations within the 14-3-3 binding pocket could serve to inhibit the entire signaling hub of 14-3-3—effectively shutting down the entire pro-cancer program of 14-3-3 with a single hit.