Joshua L. Anderson
The health of an organism is linked to the tightly regulated balance between cell proliferation and cell death. Any aberrant tilt in this balance can lead to devastating human diseases. For example, excessive proliferation unbalanced by cell death leads to cancer. On the opposite end of the spectrum, excessive cell death unbalanced by proliferation causes degenerative diseases such as Alzheimer’s, Parkinson’s and Amyotrophic Lateral Sclerosis. In the Andersen lab we use a combination of molecular and proteomics approaches to understand the mechanisms that govern this balance and how they go awry in disease. A better understanding of these processes gives us the tools to develop more targeted and effective therapies. Our recent work focuses on the following diseases/mechanisms:
The mechanisms by which cancer cells develop resistance to therapy: Chemotherapy is the primary mode of treatment for the majority of cancers and is often the only viable treatment option. Although the initial tumor response to chemotherapy is generally positive, many tumors possess a dynamic ability to adapt and develop resistance to chemotherapy (termed “chemoresistance”), which is the most common cause of patient mortality. A major roadblock to solving this problem is our fragmented understanding of the mechanisms that cause chemoresistance in tumors. To address this problem, a central project in our lab focuses on the protein 14-3-3z, a cellular hub that orchestrates many chemoresistance-promoting mechanisms. We have approached 14-3-3 from several angles, including the direct therapeutic targeting of 14-3-3z in cancer and its use as a phospho-probe to guide us to dynamic chemoresistance mechanisms. Our recent work in this area uncovered a molecular switch that activates a cellular process called autophagy, an emerging cause of chemoresistance in a variety of cancers. In addition, we recently discovered a novel mechanism that may stabilize receptor tyrosine kinases (RTKs) to promote resistance against RTK inhibitors (e.g., lapatanib, trastuzumab, gefitinib, and others). We are currently working to understand key details of these mechanisms with the ultimate goal of developing therapeutic strategies to override tumor cell resistance to therapy.
Pathogenesis of familial Amyotrophic Lateral Sclerosis: Amyotrophic lateral sclerosis (ALS) is an aggressive neurological disease that causes the death of motor neurons, progressive paralysis, and respiratory failure. Patient lifespan typically ranges between 2-5 years from diagnosis. There is no cure for ALS nor is there a way to extend patient lifespan. Although ALS is usually a sporadic disease, roughly one-tenth of ALS cases are familial (fALS). Of these, 20% are linked to mutations in the radical-scavenging enzyme superoxide dismutase-1 (SOD1). These mutations do not uniformly affect mutant SOD1 (mutSOD1) enzymatic activity, but rather are thought to confer a toxic gain-of-function. A widely accepted model is that the gain-of-function mutations convert mutSOD1 into a toxic protein that aberrantly accumulates in mitochondria, which triggers motor neuron death. However, our poor understanding of the factors that control mutSOD1 mitochondrial accumulation has made testing this model an impossibility and has been a barrier to the development of fALS therapeutics. Toward this end, our recent work has uncovered dynamic modifications on mutSOD1 that control its accumulation in mitochondria. We are currently working to understand how these modifications are regulated and whether they can be targeted for therapeutic benefit in fALS.