Cancer burden is controlled by mural cell-β3-integrin regulated crosstalk with tumor cells

Ping-Pui Wong; Jose M Munoz-Felix; Maruan Hijazi; Hyojin  Kim; Stephen Robinson; Beatriz  De Luxan-Delgado; Irene Rodiguez-Hernandez; Oscar Maiques; Ya-Ming Meng; Qiong Meng; Natalia Bodrug; Matthew Scott Dukinfield; Louise E Reynolds; George Elia; Andrew Clear; Catherine Harwood; Yu Wang; James J Campbell; Rajinder Singh; Penglie Zhang; Thomas J Schall; Kylie P Matchett; Neil Henderson; Peter W Szlosarek; Sally Dreger; Sally Smith; Louise Jones; John G Gribben; Pedro R Cutillas; Pascal Meier; Victoria Sanz-Moreno; Kairbaan Hodivala-Dilke

doi:10.1016/j.cell.2020.02.003

Cancer burden is controlled by mural cell-β3-integrin regulated crosstalk with tumor cells

Ping-Pui Wong, Jose M Munoz-Felix, Maruan Hijazi, Hyojin Kim, Stephen Robinson, Beatriz De Luxan-Delgado, Irene Rodiguez-Hernandez, Oscar Maiques, Ya-Ming Meng, Qiong Meng, Natalia Bodrug, Matthew Scott Dukinfield, Louise E Reynolds, George Elia, Andrew Clear, Catherine Harwood, Yu Wang, James J Campbell, Rajinder Singh, Penglie ZhangThomas J Schall, Kylie P Matchett, Neil Henderson, Peter W Szlosarek, Sally Dreger, Sally Smith, Louise Jones, John G Gribben, Pedro R Cutillas, Pascal Meier, Victoria Sanz-Moreno, Kairbaan Hodivala-Dilke

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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.

Original language	English
Pages (from-to)	1346-1363.e21
Number of pages	18
Journal	Cell
Volume	181
Issue number	6
Early online date	29 May 2020
DOIs	https://doi.org/10.1016/j.cell.2020.02.003
Publication status	Published - 11 Jun 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

mural cell
paracrine
β3-integrin

Access to Document

10.1016/j.cell.2020.02.003

CELL-D-18-01297_R4 (2)22Accepted author manuscript, 15.7 MBLicence: CC BY-NC-ND

Cite this

Wong, P.-P., Munoz-Felix, J. M., Hijazi, M., Kim, H., Robinson, S., De Luxan-Delgado, B., Rodiguez-Hernandez, I., Maiques, O., Meng, Y.-M., Meng, Q., Bodrug, N., Dukinfield, M. S., Reynolds, L. E., Elia, G., Clear, A., Harwood, C., Wang, Y., Campbell, J. J., Singh, R., ... Hodivala-Dilke, K. (2020). Cancer burden is controlled by mural cell-β3-integrin regulated crosstalk with tumor cells. Cell, 181(6), 1346-1363.e21. https://doi.org/10.1016/j.cell.2020.02.003

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title = "Cancer burden is controlled by mural cell-β3-integrin regulated crosstalk with tumor cells",

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.",

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author = "Ping-Pui Wong and Munoz-Felix, {Jose M} and Maruan Hijazi and Hyojin Kim and Stephen Robinson and {De Luxan-Delgado}, Beatriz and Irene Rodiguez-Hernandez and Oscar Maiques and Ya-Ming Meng and Qiong Meng and Natalia Bodrug and Dukinfield, {Matthew Scott} and Reynolds, {Louise E} and George Elia and Andrew Clear and Catherine Harwood and Yu Wang and Campbell, {James J} and Rajinder Singh and Penglie Zhang and Schall, {Thomas J} and Matchett, {Kylie P} and Neil Henderson and Szlosarek, {Peter W} and Sally Dreger and Sally Smith and Louise Jones and Gribben, {John G} and Cutillas, {Pedro R} and Pascal Meier and Victoria Sanz-Moreno and Kairbaan Hodivala-Dilke",

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month = jun,

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doi = "10.1016/j.cell.2020.02.003",

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Wong, P-P, Munoz-Felix, JM, Hijazi, M, Kim, H, Robinson, S, De Luxan-Delgado, B, Rodiguez-Hernandez, 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, N, Szlosarek, PW, Dreger, S, Smith, S, Jones, L, Gribben, JG, Cutillas, PR, Meier, P, Sanz-Moreno, V & Hodivala-Dilke, K 2020, 'Cancer burden is controlled by mural cell-β3-integrin regulated crosstalk with tumor cells', Cell, vol. 181, no. 6, pp. 1346-1363.e21. https://doi.org/10.1016/j.cell.2020.02.003

TY - JOUR

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AU - Wong, Ping-Pui

AU - Munoz-Felix, Jose M

AU - Hijazi, Maruan

AU - Kim, Hyojin

AU - Robinson, Stephen

AU - De Luxan-Delgado, Beatriz

AU - Rodiguez-Hernandez, Irene

AU - Maiques, Oscar

AU - Meng, Ya-Ming

AU - Meng, Qiong

AU - Bodrug, Natalia

AU - Dukinfield, Matthew Scott

AU - Reynolds, Louise E

AU - Elia, George

AU - Clear, Andrew

AU - Harwood, Catherine

AU - Wang, Yu

AU - Campbell, James J

AU - Singh, Rajinder

AU - Zhang, Penglie

AU - Schall, Thomas J

AU - Matchett, Kylie P

AU - Henderson, Neil

AU - Szlosarek, Peter W

AU - Dreger, Sally

AU - Smith, Sally

AU - Jones, Louise

AU - Gribben, John G

AU - Cutillas, Pedro R

AU - Meier, Pascal

AU - Sanz-Moreno, Victoria

AU - Hodivala-Dilke, Kairbaan

PY - 2020/6/11

Y1 - 2020/6/11

N2 - 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.

AB - 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.

KW - mural cell

KW - paracrine

KW - β3-integrin

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U2 - 10.1016/j.cell.2020.02.003

DO - 10.1016/j.cell.2020.02.003

M3 - Article

SN - 0092-8674

VL - 181

SP - 1346-1363.e21

JO - Cell

JF - Cell

IS - 6

ER -

Cancer burden is controlled by mural cell-β3-integrin regulated crosstalk with tumor cells

Abstract

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Keywords

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Stephen Robinson

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