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

Alvaro Román-Fernández; Mohammed A. Mansour; Fernanda G. Kugeratski; Jayanthi Anand; Emma Sandilands; Laura Galbraith; Kai Rakovic; Eva C. Freckmann; Erin M. Cumming; Ji Park; Konstantina Nikolatou; Sergio Lilla; Robin Shaw; David Strachan; Susan Mason; Rachana Patel; Lynn McGarry; Archana Katoch; Kirsteen J. Campbell; Colin Nixon; Crispin J. Miller; Hing Y. Leung; John Le Quesne; James C. Norman; Sara Zanivan; Karen Blyth; David M. Bryant

doi:10.1126/sciadv.abq1858

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

Alvaro Román-Fernández, Mohammed A. Mansour, Fernanda G. Kugeratski, Jayanthi Anand, Emma Sandilands, Laura Galbraith, Kai Rakovic, Eva C. Freckmann, Erin M. Cumming, Ji Park, Konstantina Nikolatou, Sergio Lilla, Robin Shaw, David Strachan, Susan Mason, Rachana Patel, Lynn McGarry, Archana Katoch, Kirsteen J. Campbell, Colin NixonCrispin J. Miller, Hing Y. Leung, John Le Quesne, James C. Norman, Sara Zanivan, Karen Blyth, David M. Bryant

London South Bank University

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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.

Original language	English
Article number	eabq1858
Journal	Science advances
Volume	9
Issue number	5
DOIs	https://doi.org/10.1126/sciadv.abq1858 https://doi.org/10.1126/sciadv.abq1858
Publication status	Published - 3 Feb 2023

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Copyright © 2023 The Authors.

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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., ... Bryant, D. M. (2023). Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function. Science advances, 9(5), Article eabq1858. https://doi.org/10.1126/sciadv.abq1858, https://doi.org/10.1126/sciadv.abq1858

@article{6571ca41595845ed8d65f34ae446f06e,

title = "Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function",

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.",

author = "Alvaro Rom{\'a}n-Fern{\'a}ndez and Mansour, {Mohammed A.} and Kugeratski, {Fernanda G.} and Jayanthi Anand and Emma Sandilands and Laura Galbraith and Kai Rakovic and Freckmann, {Eva C.} and Cumming, {Erin M.} and Ji Park and Konstantina Nikolatou and Sergio Lilla and Robin Shaw and David Strachan and Susan Mason and Rachana Patel and Lynn McGarry and Archana Katoch and Campbell, {Kirsteen J.} and Colin Nixon and Miller, {Crispin J.} and Leung, {Hing Y.} and {Le Quesne}, John and Norman, {James C.} and Sara Zanivan and Karen Blyth and Bryant, {David M.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Authors.",

year = "2023",

month = feb,

day = "3",

doi = "10.1126/sciadv.abq1858",

language = "English",

volume = "9",

journal = "Science advances",

issn = "2375-2548",

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Román-Fernández, A, Mansour, MA, Kugeratski, FG, Anand, J, Sandilands, E, Galbraith, L, Rakovic, K, Freckmann, EC, Cumming, EM, Park, J, Nikolatou, K, Lilla, S, Shaw, R, Strachan, D, Mason, S, Patel, R, McGarry, L, Katoch, A, Campbell, KJ, Nixon, C, Miller, CJ, Leung, HY, Le Quesne, J, Norman, JC, Zanivan, S, Blyth, K & Bryant, DM 2023, 'Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function', Science advances, vol. 9, no. 5, eabq1858. https://doi.org/10.1126/sciadv.abq1858, https://doi.org/10.1126/sciadv.abq1858

TY - JOUR

T1 - Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function

AU - Román-Fernández, Alvaro

AU - Mansour, Mohammed A.

AU - Kugeratski, Fernanda G.

AU - Anand, Jayanthi

AU - Sandilands, Emma

AU - Galbraith, Laura

AU - Rakovic, Kai

AU - Freckmann, Eva C.

AU - Cumming, Erin M.

AU - Park, Ji

AU - Nikolatou, Konstantina

AU - Lilla, Sergio

AU - Shaw, Robin

AU - Strachan, David

AU - Mason, Susan

AU - Patel, Rachana

AU - McGarry, Lynn

AU - Katoch, Archana

AU - Campbell, Kirsteen J.

AU - Nixon, Colin

AU - Miller, Crispin J.

AU - Leung, Hing Y.

AU - Le Quesne, John

AU - Norman, James C.

AU - Zanivan, Sara

AU - Blyth, Karen

AU - Bryant, David M.

PY - 2023/2/3

Y1 - 2023/2/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85147457414&partnerID=8YFLogxK

U2 - 10.1126/sciadv.abq1858

DO - 10.1126/sciadv.abq1858

M3 - Article

SN - 2375-2548

VL - 9

JO - Science advances

JF - Science advances

IS - 5

M1 - eabq1858

ER -

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

Abstract

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