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Prolonged exposure to extracellular lumican restrains pancreatic adenocarcinoma growth

Abstract

We previously demonstrated that pancreatic stellate cells within pancreatic ductal adenocarcinoma (PDAC) stroma secrete lumican and its presence is associated with prolonged survival of patients with localized PDAC. Here, we observed that extracellular lumican decreases PDAC tumour cell growth in xenograft and syngeneic orthotopic animal models, and induces growth inhibition of low-passage human PDAC cells in a species-specific manner. PDAC cells grown in variant culture conditions and exposed to extracellular lumican display typical characterizations of cancer cell in a quiescent state, such as growth inhibition, apoptosis, G0/G1 arrest and chemoresistance. Importantly, extracellular lumican is associated with diminished ERK1/2 phosphorylation and increased p38 phosphorylation within PDAC cells. We further demonstrated that extracellular lumican physically binds with EGFR to trigger EGFR internalization and downregulation of EGFR and its downstream signal molecule ERK. Lumican enhances casitas B-lineage lymphoma expression, which stabilized the TGFβ Type II receptor sensitizing PDAC cells to TGFβ-mediated activation of p38 and SMAD signals. These provide a mechanism for the shift in signalling and phenotypic changes we observed after prolonged exposure to lumican. Together, our findings demonstrate that stromal lumican restrains PDAC cell growth through mediating cell entry into a quiescent state.

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Acknowledgements

This work was supported by grants from the Skip Viragh Family Foundation (to JF), the W. Smith Foundation (to JF), National Institutes of Health (NIH) grant T32CA009599 (to DR and MRP), U54 CA210181-01 'Center for Immunotherapeutic Transport Oncophysics (CITO)' grant (to EK), and CABI GE in-kind grant (to EK). This research was conducted at the MD Anderson Cancer Center for Advanced Biomedical Imaging in-part with equipment support from General Electric Healthcare.

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Correspondence to J B Fleming.

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Li, X., Kang, Y., Roife, D. et al. Prolonged exposure to extracellular lumican restrains pancreatic adenocarcinoma growth. Oncogene 36, 5432–5438 (2017). https://doi.org/10.1038/onc.2017.125

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