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Data from Notch Signaling Contributes to Lung Cancer Clonogenic Capacity In Vitro but May Be Circumvented in Tumorigenesis In Vivo
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Data from Notch Signaling Contributes to Lung Cancer Clonogenic Capacity In Vitro but May Be Circumvented in Tumorigenesis In Vivo
Data from Notch Signaling Contributes to Lung Cancer Clonogenic Capacity In Vitro but May Be Circumvented in Tumorigenesis In Vivo
JO
Joyce Osanyingbemi-Obidi
Joyce Osanyingbemi-Obidi
ID
Irina Dobromilskaya
Irina Dobromilskaya
PI
Peter B. Illei
Peter B. Illei
CH
Christine L. Hann
Christine L. Hann
CR
Charles M. Rudin
Charles M. Rudin
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3 April 2023
other
Published by
American Association for Cancer Research (AACR)
https://doi.org/10.1158/1541-7786.c.6542065
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-KRASG12D 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-KRASG12D 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. Mol Cancer Res; 9(12); 1746–54. ©2011 AACR.
Keywords
NOTCH SIGNALING
CLONOGENIC CAPACITY
CAPACITY IN VITRO
LUNG
MODEL
ONCOGENESIS
VIVO
CANCER
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