Our laboratory investigates normal and cancer epithelial cells within a three-dimensional, organ-like, context to identify new pathways that regulate organ morphogenesis and stem cell differentiation, and to use that knowledge to identify new strategies to control and prevent cancer. We accomplish this goal by developing and using organoid culture systems to grow normal or tumor epithelial cells from organs such as breast, pancreas and prostate as mini-organs. These mini-organs bridge the gap between monolayer cell culture and in vivo conditions and provide a tractable model system to understand dynamics of cell behavior during both tissue morphogenesis and cancer cell growth.
Using organoid cultures, we have identified cell polarity proteins such as, SCRIB, PARD3 and PARD6 as key regulators of tumorigenesis regulated by oncogenes such as ERBB2 and MYC. These cell polarity proteins regulate cell death and cell-cell cohesion pathways and polarization changes during initiation of tumor and progression to metastasis. Research projects in our laboratory continues to use 3D organoid cultures to identify how cell polarity proteins regulate signaling pathways involved in cell junctions, cell differentiation and epithelial to mesenchymal transition during cancer, initiation, progression and response to therapeutic drugs.
More recently, have developed new methods to generate pancreatic epithelial organoids from human pluripotent stem cells. This normal organoid platform creates opportunities for us to investigate signaling and cell polarity mechanisms regulating normal human pancreas development in culture and to model benign human pancreatic diseases such as pancreatitis.
Our ability to grow primary pancreatic tumor cells as tumor organoids has empowered us and to identify new therapeutic options for pancreatic cancer. Using tumor organoids, we discovered that drugs against the epigenetic regulator, EZH2, is a potential therapeutic target for pancreatic cancer and efforts are currently underway to initiate a clinical trial to translate this finding towards patient care. Last, but not least, we are expanding the tumor organoid technology to other types of solid tumors such as prostate to broaden the scope of the method. We believe that tumor organoids are likely to serve as a powerful, personalized, platform for understanding drug response and resistance mechanisms in a patient-specific manner and to translate the findings towards caring for cancer patients, one patient at a time.