Improving outcomes of gastrointestinal cancers with science
Both intrinsic and extrinsic factors underlie the aggressive behavior and hence poor prognosis of pancreatic (PDAC) and colon cancers (CRC). Intrinsically, PDAC cells are driven by strong oncogenic events including KRAS mutations and hyperactivation of the NF-kB transcription factors, which render PDAC cells highly metastatic and resistant to chemotherapy.
Extrinsically, the PDAC tumor microenvironment is highly fibrotic and rife with immune-suppressive myeloid cells. We recently found that PDAC cells “armored” themselves by activating the innate immune pathway, a self-defense mechanism that is normally summoned when cells are injured or invaded by microorganisms. PDAC cells frequently activate Interleukin-Receptor Associated Kinase 4 (IRAK4), the master switch that controls the innate immune signaling, to drive NF-kB activity and resist killing by chemotherapeutic agents. We found that patients whose tumors show upregulated IRAK4 activity have a much poorer survival, and we recently identified tumor-stromal IL-1b to be the source of IRAK4 activation in PDAC and stromal cells.
Current lab projects
- Determining whether IRAK4 inhibition will render immunotherapy effective in PDAC and colon cancer cells. We use a combination of genetically-engineered mouse models (KPC and APC min mice) and transplantable cell lines in this study. We have also generated global and conditional IRAK4-null mice for this study.
- Understanding how IRAK4 signaling impacts KRAS-RAF-MEK-ERK signaling cascade.
- Determining the role of p38/MK2 pathway in survival of PDAC cells undergoing environmental and genotoxic stress, with the goal of developing novel therapeutic strategies
- Developing effective ERK-inhibitor based therapeutic strategies based on novel observations.
- Understanding the role of IRAK4 and interaction with gut microbes in CRC mouse models.
Our lab employs multiple approaches to address these research directions with the goal of developing novel therapeutic strategies that can improve patient outcome. Our lab is funded by the ACS and NIH, and we welcome all researchers/students who are interested in checking us out!