Principal Investigator Tyler Jacks
Injury models have suggested that the lung contains anatomically and functionally distinct epithelial stem cell populations. We have isolated such a regional pulmonary stem cell population, termed bronchioalveolar stem cells (BASCs). These stem cells were enriched, propagated, and differentiated in vitro and found to be activated by the oncogenic protein K-ras (Kim et al., 2005). Our studies suggest that BASCs are a stem cell population that maintains the bronchiolar Clara cells and alveolar cells of the distal lung and that their transformed counterparts give rise to adenocarcinoma.
Kras is also commonly mutated in colon cancers, but mutations in Nras are rare. We have used genetically engineered mice to determine whether and how these related oncogenes regulate homeostasis and tumorigenesis in the colon. Expression of K-RasG12D in the colonic epithelium stimulated hyperproliferation in a Mek-dependent manner. N-RasG12D did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc-mutant colonic tumor, activation of K-Ras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium (Haigis et al., 2008).
Finally, Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal of all human malignancies. Currently, there are no reliable means for early detection or effective treatment options. Pancreatic ductal adenocarcinoma has a particularly high incidence of activating K-RAS mutations, which are believed to be an initiating event. Identification and characterization of the cell of origin(s) of PDAC is essential for elucidating the pathways affected by oncogenic mutations early in tumor development, at a point when chemopreventative measures might still be effective. Insight into the complex aspects of PDAC biology should also result in improved detection and diagnosis of this devastating disease.