Our laboratory researches how cancer cells develop drug resistance, and more specifically, how the tumor microenvironment provides support and protection to tumor cells. Results from these studies will allow us to develop better strategies to overcome drug resistance by finding more effective therapies for the treatment of cancer.

Our previous research suggests that tumor microenvironment plays a critical role in protecting cancer cells from drug treatments, and part of our research is aimed at finding drug targets in the tumor microenvironment that could be either used to circumvent the development of drug resistance or prevent the protective signals from the microenvironment from reaching the tumor cells. As an alternative approach we are also identifying molecules within the tumor cells themselves that regulate the emergence of drug resistance, and developing ways to target these molecules.

We are currently investigating these topics in the context of breast and pancreatic cancer. In breast cancer we are studying the tumor microenvironment mediated resistance mechanisms towards PI3K/mTOR and CDK4/6 inhibitors. PI3K/mTOR-pathway is one of the most commonly mutated pathways in cancer. It is estimated that approximately ~70% of cancers have this pathway activated. Therefore it is a very attractive target for cancer therapy, and recently the first drug targeting this pathway was FDA approved for the treatment of breast cancer. Our previous work (Muranen et al, Cancer Cell, 2012) identified a context specific emergence of drug resistance, where tumor cells which were adhered to extracellular matrix (stroma) survived drug treatments and developed resistance, whereas tumor cells without matrix attachment died. This indicated that matrix attachment provides critical survival cues for tumor cells and promotes emergence of drug resistance. These data led us to investigate in more detail how adhesion to matrix regulates drug resistance and identifying molecules that could be targeted to overcome this resistance. 

Our more recent data shows that matrix contact also protects normal cells from stressful stimuli and that normal epithelial cells can ‘eat’ matrix proteins to survive periods of starvation and stress (Muranen et al. Nature Communications 2017). We are currently interested in identifying similarities and differences between these two programs in tumor cells vs. normal cells to identify tumor specific vulnerabilities that could be used to target tumor cells specifically. These data also led us to study pancreatic cancer which is one of the most lethal types of cancer, extremely abundant in matrix proteins, and resistant to all therapies. We are currently studying the crosstalk between the stromal cells of the pancreas and the pancreatic cancer cells, and we have identified several candidate proteins that promote cancer cell fitness that we will target therapeutically.

To investigate these topics we utilize both normal and cancer cells in three-dimensional cell culture systems, which mimic the architecture and organization of living tissues much more accurately than traditional two-dimensional tissue culture systems. We use this platform in co-culture systems to understand how stromal and epithelial cells communicate with each other, and have also adopted the use of this 3D platform to do proteomics and metabolomics studies to gain insight into multiple pathways and mechanisms the cells use when becoming drug resistant.