title: Notch signaling contributes to lung cancer clonogenic capacity in vitro but may be circumvented in tumorigenesis in vivo.
abstract: The Notch signaling pathway is a critical embryonic developmental regulatory pathway that has been implicated in oncogenesis. In non-small cell lung cancer (NSCLC), recent evidence suggests that Notch signaling may contribute to maintenance of a cancer stem or progenitor cell compartment required for tumorigenesis. We explored whether intact Notch signaling is required for NSCLC clonogenic and tumorigenic potential in vitro and in vivo using a series of genetically modified model systems. In keeping with previous observations, we find that Notch3 in particular is upregulated in human lung cancer lines and that downregulation of Notch signaling using a selective γ-secretase inhibitor (MRK-003) is associated with decreased proliferation and clonogenic capacity in vitro. We show that this phenotype is rescued with the expression of NICD3, a constitutively active cleaved form of Notch3 not affected by γ-secretase inhibition. Using an inducible LSL-KRAS(G12D) model of lung cancer in vivo, we show a transient upregulation of Notch pathway activity in early tumor precursor lesions. However, a more rigorous test of the requirement for Notch signaling in lung oncogenesis, crossing the LSL-KRAS(G12D) mouse model with a transgenic with a similarly inducible global dominant-negative suppressor of Notch activity, LSL-DNMAML (dominant-negative mastermind-like), reveals no evidence of Notch pathway requirement for lung tumor initiation or growth in vivo. Distinct Notch family members may have different and potentially opposing activities in oncogenesis, and targeted inhibition of individual Notch family members may be a more effective anticancer strategy than global pathway suppression.
authors: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
authors: Joyce
authors: J
authors: Osanyingbemi-Obidi
authors: Irina
authors: I
authors: Dobromilskaya
authors: Peter B
authors: PB
authors: Illei
authors: Christine L
authors: CL
authors: Hann
authors: Charles M
authors: CM
authors: Rudin
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D003114:Colony-Forming Units Assay; D003499:Cyclic S-Oxides / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: D003499:Cyclic S-Oxides; C523799:MRK 003; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D013830:Thiadiazoles; D053829:Amyloid Precursor Protein Secretases