Ligand-independent integrin β1 signaling supports lung adenocarcinoma development
Scott M. Haake, Erin J. Plosa, Jonathan A. Kropski, Lindsay A. Venton, Anupama Reddy, Fabian Bock, Betty T. Chang, Allen J. Luna, Kateryna Nabukhotna, Zhi-Qi Xu, Rebecca A. Prather, Sharon Lee, Harikrishna Tanjore, Vasiliy V. Polosukhin, Olga M. Viquez, Angela Jones, Wentian Luo, Matthew H. Wilson, W. Kimryn Rathmell, Pierre P. Massion, Ambra Pozzi, Timothy S. Blackwell, Roy Zent
Scott M. Haake, Erin J. Plosa, Jonathan A. Kropski, Lindsay A. Venton, Anupama Reddy, Fabian Bock, Betty T. Chang, Allen J. Luna, Kateryna Nabukhotna, Zhi-Qi Xu, Rebecca A. Prather, Sharon Lee, Harikrishna Tanjore, Vasiliy V. Polosukhin, Olga M. Viquez, Angela Jones, Wentian Luo, Matthew H. Wilson, W. Kimryn Rathmell, Pierre P. Massion, Ambra Pozzi, Timothy S. Blackwell, Roy Zent
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Research Article Oncology

Ligand-independent integrin β1 signaling supports lung adenocarcinoma development

Abstract

Integrins — the principal extracellular matrix (ECM) receptors of the cell — promote cell adhesion, migration, and proliferation, which are key events for cancer growth and metastasis. To date, most integrin-targeted cancer therapeutics have disrupted integrin-ECM interactions, which are viewed as critical for integrin functions. However, such agents have failed to improve cancer patient outcomes. We show that the highly expressed integrin β1 subunit is required for lung adenocarcinoma development in a carcinogen-induced mouse model. Likewise, human lung adenocarcinoma cell lines with integrin β1 deletion failed to form colonies in soft agar and tumors in mice. Mechanistically, we demonstrate that these effects do not require integrin β1–mediated adhesion to ECM but are dependent on integrin β1 cytoplasmic tail-mediated activation of focal adhesion kinase (FAK). These studies support a critical role for integrin β1 in lung tumorigenesis that is mediated through constitutive, ECM binding–independent signaling involving the cytoplasmic tail.

Authors

Scott M. Haake, Erin J. Plosa, Jonathan A. Kropski, Lindsay A. Venton, Anupama Reddy, Fabian Bock, Betty T. Chang, Allen J. Luna, Kateryna Nabukhotna, Zhi-Qi Xu, Rebecca A. Prather, Sharon Lee, Harikrishna Tanjore, Vasiliy V. Polosukhin, Olga M. Viquez, Angela Jones, Wentian Luo, Matthew H. Wilson, W. Kimryn Rathmell, Pierre P. Massion, Ambra Pozzi, Timothy S. Blackwell, Roy Zent

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Figure 1

Deletion of integrin β1 in type 2 alveolar epithelial cells results in development of fewer tumors.

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Deletion of integrin β1 in type 2 alveolar epithelial cells results in d...
(A) Tumorigenesis was initiated with urethane in integrin β1fl/0 mice without (control, n = 7) and with (integrin β1–KO, n = 8) dox-inducible SPC rtTA;TetO-Cre. (B) Representative photograph of formalin-inflated lungs (removed en bloc with heart/mediastinum) demonstrating fewer tumors in the integrin β1–KO mice relative to the control mice (arrow heads, tumor). Scale bar: 1 cm. (C) Quantitation of tumor count across the entire cohort. (D) Longest diameter of all tumors from integrin β1–KO and control mice is graphed. (E) Both control and integrin β1–KO mice developed lesions across the spectrum of disease, with representative photomicrographs shown of atypical alveolar hyperplasia, adenomas, and adenocarcinomas. Scale bar: 500 μm. Lesions that developed in the WT and integrin β1–KO mice were histologically indistinguishable, and the lesions shown are representative of those that developed in either strain of mouse. (F and G) FFPE tumors from control and integrin β1–KO mice were stained for integrin β1 with representative photomicrographs shown (n = 5). Scale bar: 50 μm. (H) Single-cell RNA-Seq was performed on tumors and adjacent normal tissue (tissue was pooled for n = 2 mice from each genotype). Uniform manifold approximation and projection (UMAP) depicting epithelial-like cells isolated from tumors or adjacent tissue from integrin β1–KO and control mouse lungs are shown. (I) Relative levels of integrin β1 (Itgb1) gene expression is shown for AT1, AT2, and tumor cells. *P < 0.05 by unpaired, 2-tailed t test. Data are shown as mean ± SEM.