We combine molecular and biochemical approaches with proteomics to discover mechanisms that control tumor cell growth and survival. A better understanding of these mechanisms gives us tools to develop more effective and targeted cancer therapies.
Decoding the language of cell signaling
All of the projects in our lab are linked together by a common interest in cell signaling—specifically, how dynamic post-translational modifications (PTMs) control all aspects of tumor cell biology, including immune signaling, cell survival, metastasis, and growth.
This is a daunting challenge. Modern proteomics has uncovered over 600,000 PTMs across the human proteome and these PTMs come in more than 200 varieties. However, we only know the function of a tiny fraction of these PTMs, which limits our ability to design targeted therapeutics. We tackle this challenge with a variety of approaches that include the following major projects:
1) Harnessing the oncogenic phospho-binding protein 14-3-3 as a biological probe to identify mechanisms of tumor cell growth and survival. 14-3-3 proteins interact dynamically with phosphorylated "client" proteins to control essentially every major cellular process. Our lab harnesses 14-3-3 as a proteomics probe to quickly identify functional phosphorylations (drilling through the noise in the phospho-proteome) that control important aspects of tumor biology. This approach has been a source of many fruitful projects in the lab, including recent publications on autophagy, kinase biology, and cell cycle regulators.
2) Discovering the function and regulatory mechanisms of understudied kinases. In order for a cell to become cancerous, it must acquire (e.g., via mutation) the activity of pro-growth kinases. Yet despite the importance of kinases as therapeutic targets in cancer, over 25% of the 634 kinases in our cells are still understudied, leaving over 100 kinases untapped as potential therapeutic targets. Our recent work in this area has focused on the enigmatic ACK family (TNK1 and ACK1) of tyrosine kinases. We recently published the first mechanistic study on TNK1, which described how TNK1 is regulated by phosphorylation and also interacts directly with poly-ubiquitin chains. This study also included the development of an anti-TNK1 small molecule with in vivo activity against TNK1-driven tumors. Our current efforts in this area focus on understanding the biological function/regulation of TNK1 and ACK1, and developing strategies to target these kinases in cancer patients.
3) Uncovering mechanisms of basal autophagy. Tumor cells rely on basal autophagy to rid themselves of toxic protein aggregates, defective mitochondria, and other cellular debris. However, the core mechanisms of basal autophagy are still poorly understood. Our recent work focuses on how the first steps in basal autophagy are regulated, and how disruption of these steps activates pro-inflammatory signaling—a vulnerability that we are trying to exploit to improve cancer treatment.
4) Developing computational approaches to more efficiently identify PTMs that control cancer cell fate. There are over 600,000 PTMs in the human proteome and only a small fraction of these PTMs have a biological function when tested in the lab. Thus, identifying important, functional PTMs can be a needle-in-a-haystack challenge (also very costly!). To help overcome this challenge, we are using machine learning approaches that consider aspects of protein structure and sequence, cancer-associated mutations, and PTM proteomics data to quickly identify functional PTMs.