Thrombospondin-1 mediates oncogenic Ras–induced senescence in premalignant lung tumors
Kwan-Hyuck Baek, … , Gerard I. Evan, Sandra Ryeom
Kwan-Hyuck Baek, … , Gerard I. Evan, Sandra Ryeom
Published September 9, 2013
Citation Information: J Clin Invest. 2013;123(10):4375-4389. https://doi.org/10.1172/JCI67465.
View: Text | PDF
Research Article Oncology

Thrombospondin-1 mediates oncogenic Ras–induced senescence in premalignant lung tumors

Abstract

Progression of premalignant lesions is restrained by oncogene-induced senescence. Oncogenic Ras triggers senescence in many organs, including the lung, which exhibits high levels of the angiogenesis inhibitor thrombospondin-1 (TSP-1). The contribution of TSP-1 upregulation to the modulation of tumorigenesis in the lung is unclear. Using a mouse model of lung cancer, we have shown that TSP-1 plays a critical and cell-autonomous role in suppressing Kras-induced lung tumorigenesis independent of its antiangiogenic function. Overall survival was decreased in a Kras-driven mouse model of lung cancer on a Tsp-1–/– background. We found that oncogenic Kras–induced TSP-1 upregulation in a p53-dependent manner. TSP-1 functioned in a positive feedback loop to stabilize p53 by interacting directly with activated ERK. TSP-1 tethering of ERK in the cytoplasm promoted a level of MAPK signaling that was sufficient to sustain p53 expression and a senescence response. Our data identify TSP-1 as a p53 target that contributes to maintaining Ras-induced senescence in the lung.

Authors

Kwan-Hyuck Baek, Dongha Bhang, Alexander Zaslavsky, Liang-Chuan Wang, Anil Vachani, Carla F. Kim, Steven M. Albelda, Gerard I. Evan, Sandra Ryeom

×

Figure 1

Loss of TSP-1 leads to decreased survival and rapid progression of KrasG12D-mediated lung tumorigenesis.

Options: View larger image (or click on image) Download as PowerPoint
Loss of TSP-1 leads to decreased survival and rapid progression of KrasG...
(A) Overall KrasG12D×Tsp-1+/+ and KrasG12D×Tsp-1–/– mouse survival after induction of KrasG12D expression via intranasal instillation of Ad-Cre. Data represent mean ± SEM. P = 0.0064. (B) H&E images of lungs at the indicated times after oncogenic Kras activation. Lungs were harvested, stained with H&E, and scored for tumor pathology. (C) TSP-1 expression in oncogenic KrasG12D-driven lung lesions at the indicated times after Ad-Cre infection. Isolated KrasG12D×Tsp-1+/+ lungs were examined for TSP-1 expression by immunofluorescence. KrasG12D×Tsp-1–/– lung tumors were immunostained for TSP-1 as a negative control. Corresponding H&E images of tumors are shown below. AAH, atypical adenomatous hyperplasia. (D) Time course analysis of TSP-1 expression upon oncogenic Kras activation in primary murine adult lung fibroblasts. KrasG12D×Tsp-1+/+ lung fibroblasts were infected with Ad-Cre, harvested at the indicated time points, and analyzed for TSP-1 expression by immunoblotting. KrasG12D×Tsp-1–/– fibroblasts served as a negative control. (E) Representative images of TSP-1 expression by immunofluorescence in normal human lungs and lung adenocarcinomas at different stages. Scale bars: 1 mm (B, ×40); 50 μm (B, ×400; C; and E).