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An integrin ??-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition.

ABSTRACT: Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin ?(v)?? serves as a marker of breast, lung and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumour xenografts or in clinical specimens from lung cancer patients who had progressed on erlotinib. Mechanistically, ?(v)??, in the unliganded state, recruits KRAS and RalB to the tumour cell plasma membrane, leading to the activation of TBK1 and NF-?B. In fact, ?(v)?? expression and the resulting KRAS-RalB-NF-?B pathway were both necessary and sufficient for tumour initiation, anchorage independence, self-renewal and erlotinib resistance. Pharmacological targeting of this pathway with bortezomib reversed both tumour stemness and erlotinib resistance. These findings not only identify ?(v)?? as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy to sensitize such tumours to RTK inhibition.

SUBMITTER: Seguin L

PROVIDER: S-EPMC4105198 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition.

Seguin Laetitia L Seguin Laetitia L Kato Shumei S Franovic Aleksandra A Camargo M Fernanda MF Lesperance Jacqueline J Elliott Kathryn C KC Yebra Mayra M Mielgo Ainhoa A Lowy Andrew M AM Husain Hatim H Cascone Tina T Diao Lixia L Wang Jing J Wistuba Ignacio I II Heymach John V JV Lippman Scott M SM Desgrosellier Jay S JS Anand Sudarshan S Weis Sara M SM Cheresh David A DA

Nature cell biology 20140420 5

Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin α(v)β₃ serves as a marker of breast, lung and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumour xenografts or in clinical specimens from lung cancer patients who had progressed on erlotinib. Mechanistically, α(v)β₃, in the ...[more]

PMID: 24747441

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Project description:The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/?1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/?1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/?1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and ?1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/?1 complex to maintain the high-affinity ?1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/?1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced ?5 integrin from ?1 integrin, creating a complex with much greater affinity for fibronectin (FN) than ?5?1. Thus, tumor cells adapt to microenvironmental stressors induced by metastases or bevacizumab by coopting receptors, which normally promote both cell migration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/?1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.

Dataset Information

An integrin ??-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition.

Publications

An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition.

Similar Datasets

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