Although mutations in Kras are present in 21% of lung tumors, there is a high level of heterogeneity in phenotype and outcome among patients with lung cancer bearing similar mutations, suggesting that other pathways are important. Wnt/β-catenin signaling is a known oncogenic pathway that plays a well-defined role in colon and skin cancer; however, its role in lung cancer is unclear. We have shown here that activation of Wnt/β-catenin in the bronchiolar epithelium of the adult mouse lung does not itself promote tumor development. However, concurrent activation of Wnt/β-catenin signaling and expression of a constitutively active Kras mutant (KrasG12D) led to a dramatic increase in both overall tumor number and size compared with KrasG12D alone. Activation of Wnt/β-catenin signaling altered the KrasG12D tumor phenotype, resulting in a phenotypic switch from bronchiolar epithelium to the highly proliferative distal progenitors found in the embryonic lung. This was associated with decreased E-cadherin expression at the cell surface, which may underlie the increased metastasis of tumors with active Wnt/β-catenin signaling. Together, these data suggest that activation of Wnt/β-catenin signaling can combine with other oncogenic pathways in lung epithelium to produce a more aggressive tumor phenotype by imposing an embryonic distal progenitor phenotype and by decreasing E-cadherin expression. IntroductionLung cancer is the second most common cancer in both men and women, accounting for approximately 15% of all newly diagnosed cancers (1, 2). Despite extensive investment of research dollars into developing new treatments for lung cancer, it remains responsible for 29% of cancer deaths in the United States, which is more than breast, colon, and prostate cancer combined. The overall 5-year survival rate is only 15.8%, making lung cancer one of the most deadly and difficult to diagnose cancers in humans.Although smoking is the primary cause of most lung cancer, approximately 10%-15% of lung cancers are found in nonsmokers, suggesting additional genetic causes of this disease. Extensive research into the underlying molecular insults leading to lung epithelial oncogenesis has resulted in the finding that Kras and EGFR mutations account for a large number of pulmonary cancers (3-7). However, there is significant heterogeneity among patients with similar mutations, suggesting the contribution of additional molecular pathways in the regulation of lung oncogenesis.Wnt/β-catenin signaling is a well-described oncogenic pathway that plays important roles in several cancers, including colon cancer, where it is the most common genetic cause of oncogenesis (8, 9). The role of Wnt/β-catenin signaling in lung cancer remains somewhat unclear. Mutations in β-catenin and adenomatous polyposis coli (APC), the most commonly mutated factors found in other cancers, are found only rarely in human lung tumors, and previous mouse models of Wnt/β-catenin activation in the postnatal

Aberrant Kras signaling is observed in a high percentage of human lung cancers while activating mutations in the Wnt/β-catenin signaling pathway are only rarely found. Our recent work has shown that the combined activation of both Kras and Wnt/β-catenin signaling leads to a dramatic increase in both tumor incidence and size. Moreover, lung tumors generated by the combined activation of both of these pathways exhibit a distinct phenotype similar to embryonic progenitors found in the developing lung. Thus, combinatorial activation of Kras and Wnt/β-catenin pathways leads to a significant increase in lung tumor formation characterized by a more progenitor like phenotype.

The extraocular muscles (EOMs) are a distinct muscle group that displays an array of unique contractile, structural, and regenerative properties. They also have differential sensitivity to certain diseases and are enigmatically spared in Duchenne muscular dystrophy (DMD). The EOMs are so distinct from other skeletal muscles that the term "allotype" has been coined to highlight EOM group-specific properties. We hypothesized that increased and distinct stem cells may underlie the continual myogenesis noted in EOM. The side population (SP) stem cells were isolated and studied. EOMs had 15x higher SP cell content compared with limb muscles. Expression profiling revealed 348 transcripts that define the EOM-SP transcriptome. Over 92% of transcripts were SP specific, because they were absent in previous whole muscle microarray studies. Cultured EOM-SP cells revealed superior in vitro proliferative capacity. Finally, assays of the committed progenitors or satellite cells performed on myofibers isolated from EOM and limb muscles independently validated the increased proliferative capacity of these muscles. We suggest a model in which unique EOM stem cells contribute to the continual myogenesis noted in EOM and consistent with a role for their sparing in DMD. We believe the greater numbers of stem cells, their unique transcriptome, the greater proliferative capacity of EOM stem cells, and the greater number of satellite cells also offer clues for novel cell-based therapeutic strategies.

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