Cancer Burden Is Controlled by Mural Cell-β3-Integrin Regulated Crosstalk with Tumor Cells.

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ICR Authors

Meier, Pascal

Authors

Wong, P-P
Muñoz-Félix, JM
Hijazi, M
Kim, H
Robinson, SD
De Luxán-Delgado, B
Rodríguez-Hernández, I
Maiques, O
Meng, Y-M
Meng, Q
Bodrug, N
Dukinfield, MS
Reynolds, LE
Elia, G
Clear, A
Harwood, C
Wang, Y
Campbell, JJ
Singh, R
Zhang, P
Schall, TJ
Matchett, KP
Henderson, NC
Szlosarek, PW
Dreger, SA
Smith, S
Jones, JL
Gribben, JG
Cutillas, PR
Meier, P
Sanz-Moreno, V
Hodivala-Dilke, KM

Document Type

Journal Article

Date

2020-06-11

Date Accepted

2020-01-31

Abstract

Enhanced blood vessel (BV) formation is thought to drive tumor growth through elevated nutrient delivery. However, this observation has overlooked potential roles for mural cells in directly affecting tumor growth independent of BV function. Here we provide clinical data correlating high percentages of mural-β3-integrin-negative tumor BVs with increased tumor sizes but no effect on BV numbers. Mural-β3-integrin loss also enhances tumor growth in implanted and autochthonous mouse tumor models with no detectable effects on BV numbers or function. At a molecular level, mural-cell β3-integrin loss enhances signaling via FAK-p-HGFR-p-Akt-p-p65, driving CXCL1, CCL2, and TIMP-1 production. In particular, mural-cell-derived CCL2 stimulates tumor cell MEK1-ERK1/2-ROCK2-dependent signaling and enhances tumor cell survival and tumor growth. Overall, our data indicate that mural cells can control tumor growth via paracrine signals regulated by β3-integrin, providing a previously unrecognized mechanism of cancer growth control.

Citation

Cell, 2020, 181 (6), pp. 1346 - 1363.e21

DOI

10.1016/j.cell.2020.02.003

URI

https://repository.icr.ac.uk/handle/internal/4114

Rights

Source Title

Publisher

CELL PRESS

ISSN

0092-8674

eISSN

1097-4172

Collections

Breast Cancer Research

Research Team

Cell Death and Immunity

Notes