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Projects

MacKeigan Laboratory

Autophagy

(resistance to cell death)

Autophagy functions to generate energy, clear damaged organelles, and delay or prevent cell death
during times of cellular stress. Chemotherapeutic agents trigger autophagy, allowing cancer cells to adapt and withstand treatment. Therefore, a better understanding of autophagy is critical for developing new and improved treatment strategies in cancer. Our lab has used predictive computational modeling and cell-based measurements to accurately model the autophagic process. We are now validating and extending our model to predict the therapeutic benefit of inhibiting autophagy in cancer. Additionally, our group conducts optimized kinase and phosphatase assays for in vitro evaluation of compounds identified in silico. Our research suggests that these kinase inhibitors modulate autophagy, and may be more selective and effective than current lysomotropic agents.autophagy steps molecular details

Cancer metabolism

(dysregulated cellular energetics)

Aggressive cancers are well-known for their altered metabolic profiles and ability to withstand cytotoxic therapies. As such, defining the relationship between dysregulated metabolism and evasion of apoptosis represents a critical need and gap in knowledge in the cancer field. Our research suggests that increased glycolysis leads to significant enrichment of the mitochondrial lipid, cardiolipin (CL), in cancer cells. CL is a well-characterized phospholipid and serves many important functions in maintaining mitochondrial health; most intriguing, however, is CL’s role in preventing release of cytochrome c. Because cytochrome c release is a key event during apoptosis, we are investigating whether increased CL allows cancer cells to avoid death and resist chemotherapy.

FIGURE 1 R01 Ren - CL Function in the Mito

Tuberous Sclerosis Complex

(molecular pathway expertise)

Tuberous sclerosis complex is a genetic disease resulting from mutations in the TSC1 and TSC2 genes. The disease causes non-cancerous tumors in vital organs throughout the body, such as the brain, skin, eyes and heart. These tumors can cause a host of health issues, including epilepsy and autism. Our lab is characterizing the genomic landscape of TSC tumors using next-generation sequencing. We have gained a more comprehensive understanding of TSC tumor biology, and we are investigating whether novel, clinically actionable aberrations exist. TSC tumors are not always associated with second-hit somatic mutations to TSC1 or TSC2, suggesting that their pathogenesis may involve additional genetic events, which we are currently working to uncover. Learn more about our TSC research and our Pathway of Hope of project here.

Figure 2