Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function

Román-Fernández, A. et al. (2023) Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function. Science Advances, 9(5), eabq1858. (doi: 10.1126/sciadv.abq1858) (PMID:36735782) (PMCID:PMC9897673)

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The glycocalyx component and sialomucin podocalyxin (PODXL) is required for normal tissue development by promoting apical membranes to form between cells, triggering lumen formation. Elevated PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumor types. How PODXL presents this duality in effect remains unknown. We identify an unexpected function of PODXL as a decoy receptor for galectin-3 (GAL3), whereby the PODXL-GAL3 interaction releases GAL3 repression of integrin-based invasion. Differential cortical targeting of PODXL, regulated by ubiquitination, is the molecular mechanism controlling alternate fates. Both PODXL high and low surface levels occur in parallel subpopulations within cancer cells. Orthotopic intraprostatic xenograft of PODXL-manipulated cells or those with different surface levels of PODXL define that this axis controls metastasis in vivo. Clinically, interplay between PODXL-GAL3 stratifies prostate cancer patients with poor outcome. Our studies define the molecular mechanisms and context in which PODXL promotes invasion and metastasis.

Item Type:Articles
Additional Information:This work was supported by the following grants: NIH K99CA163535 and CRUK (C596/A19481) (to D.M.B.), CRUK (C596/A17196 and A31287) (to E.S., A.R.-F., L.M., A.K., and D.S.), Royal Society (NF161630) (to M.A.M.), CRUK (A29801) (to C.J.M. and R.S.), CRUK (A22904) (to R.P. and H.Y.L.), CRUK (A29799 and A17196) (to S.M., J.A., K.J.C., and K.B.), CRUK (A17196 and A31287) (to J.C.N.), and CRUK (A29800) (to F.G.K. and S.Z.).
Glasgow Author(s) Enlighten ID:Roman Fernandez, Mr Alvaro and Blyth, Professor Karen and Zanivan, Professor Sara and Leung, Professor Hing and Strachan, Mr David and Mansour, Dr Mohammed Ahmed and Freckmann, Eva and Katoch, Dr Archana and Miller, Professor Crispin and Patel, Dr Rachana and Rakovic, Dr Kai and Norman, Professor James and Kugeratski, Fernanda Grande and Cumming, Erin and Nixon, Mr Colin and Lilla, Dr Sergio and McGarry, Ms Lynn and Bryant, Dr David and Campbell, Dr Kirsteen and Le Quesne, Professor John and Sandilands, Dr Emma and Nikolatou, Konstantina and Mason, Miss Susan and Galbraith, Dr Laura
Authors: Román-Fernández, A., Mansour, M. A., Kugeratski, F. G., Anand, J., Sandilands, E., Galbraith, L., Rakovic, K., Freckmann, E. C., Cumming, E. M., Park, J., Nikolatou, K., Lilla, S., Shaw, R., Strachan, D., Mason, S., Patel, R., McGarry, L., Katoch, A., Campbell, K. J., Nixon, C., Miller, C. J., Leung, H. Y., Le Quesne, J., Norman, J. C., Zanivan, S., Blyth, K., and Bryant, D. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Science Advances
Publisher:American Association for the Advancement of Science
ISSN (Online):2375-2548
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Science Advances 9(5): eabq1858
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170638Non-Clinical Training Award Cycle 2David BryantCancer Research UK (CRUK)C596/A19481Institute of Cancer Sciences
173575Dissecting the role of the metastasis-promoting protein PodocalyxinDavid BryantThe Royal Society (ROYSOC)NF161630CS - Beatson Institute for Cancer Research