Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function
Journal article
Román-Fernández, A., Mansour, M., 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, A.J., Nixon, C., Miller, D.J., Leung, H.Y., Le Quesne, J., Norman, J.C., Zanivan, S., Blyth, K. and Bryant, K.M. (2023). Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function. Science Advances. 9 (5). https://doi.org/10.1126/sciadv.abq1858
| Authors | Román-Fernández, A., Mansour, M., 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, A.J., Nixon, C., Miller, D.J., Leung, H.Y., Le Quesne, J., Norman, J.C., Zanivan, S., Blyth, K. and Bryant, K.M. |
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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. |
| Year | 2023 |
| Journal | Science Advances |
| Journal citation | 9 (5) |
| Publisher | American Association for the Advancement of Science (AAAS) |
| ISSN | 2375-2548 |
| Digital Object Identifier (DOI) | https://doi.org/10.1126/sciadv.abq1858 |
| Web address (URL) | https://doi.org/10.1126/sciadv.abq1858 |
| Publication dates | |
| Online | 03 Feb 2023 |
| Publication process dates | |
| Accepted | 03 Jan 2023 |
| Deposited | 07 Feb 2023 |
| Publisher's version | License File Access Level Open |
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