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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Abstract
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.). |
| Status: | Published |
| Refereed: | Yes |
| 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: | 2375-2548 |
| 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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