Despite advances in therapeutic approaches, lung cancer remains the leading cause of cancer-related deaths. To understand the molecular programs underlying lung cancer initiation and maintenance, we focused on stem cell programs that are normally extinguished with differentiation but can be reactivated during oncogenesis. Here, we have used extensive genetic modeling and patient-derived xenografts (PDXs) to identify a dual role for Msi2: as a signal that acts initially to sensitize cells to transformation, and subsequently to drive tumor propagation. Using Msi reporter mice, we found that Msi2-expressing cells were marked by a pro-oncogenic landscape and a preferential ability to respond to Ras and p53 mutations. Consistent with this, genetic deletion of Msi2 in an autochthonous Ras/p53-driven lung cancer model resulted in a marked reduction of tumor burden, delayed progression, and a doubling of median survival. Additionally, this dependency was conserved in human disease as inhibition of Msi2 impaired tumor growth in PDXs. Mechanistically, Msi2 triggered a broad range of pathways critical for tumor growth, including several novel effectors of lung adenocarcinoma. Collectively, these findings reveal a critical role for Msi2 in aggressive lung adenocarcinoma, lend new insight into the biology of this disease, and identify potential new therapeutic targets.

The purpose of these studies is to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, dedifferentiation of Müller glia (MG), reprogramming into proliferating MG-derived progenitor cells (MGPCs), and neuronal differentiation of the progeny of MGPCs in the chick retina. We found that S1P-related genes are highly expressed by retinal neurons and glia, and levels of expression were dynamically regulated following retinal damage. Drug treatments that activate S1P receptor 1 (S1PR1) or increase levels of S1P suppressed the formation of MGPCs. Conversely, treatments that inhibit S1PR1 or decrease levels of S1P stimulated the formation of MGPCs. Inhibition of S1P receptors or S1P synthesis significantly enhanced the neuronal differentiation of the progeny of MGPCs. We report that S1P-related gene expression in MG is modulated by microglia and inhibition of S1P receptors or S1P synthesis partially rescues the loss of MGPC formation in damaged retinas missing microglia. Finally, we show that TGFβ/Smad3 signaling in the resting retina maintains S1PR1 expression in MG. We conclude that the S1P signaling is dynamically regulated in MG and MGPCs in the chick retina, and activation of S1P signaling depends, in part, on signals produced by reactive microglia.