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

Ping-Pui Wong; José M Muñoz-Félix; Maruan Hijazi; Hyojin Kim; Stephen D Robinson; Beatriz De Luxán-Delgado; Irene Rodríguez-Hernández; 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 C Henderson; Peter W Szlosarek; Sally A Dreger; Sally Smith; J Louise Jones; John G Gribben; Pedro R Cutillas; Pascal Meier; Victoria Sanz-Moreno; Kairbaan M 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, José M Muñoz-Félix, Maruan Hijazi, Hyojin Kim, Stephen D Robinson, Beatriz De Luxán-Delgado, Irene Rodríguez-Hernández, 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 C Henderson, Peter W Szlosarek, Sally A Dreger, Sally Smith, J Louise Jones, John G Gribben, Pedro R Cutillas, Pascal Meier, Victoria Sanz-Moreno, Kairbaan M Hodivala-Dilke

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

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
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

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10.1016/j.cell.2020.02.003

Neil Henderson
- Neil.Hendersoned.acuk
- Deanery of Clinical Sciences - Personal Chair of Tissue Repair and Regeneration
- Centre for Inflammation Research
Person: Academic: Research Active (Research Assistant)

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Wong, P.-P., Muñoz-Félix, J. M., Hijazi, M., Kim, H., Robinson, S. D., De Luxán-Delgado, B., Rodríguez-Hernández, 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. M. (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

@article{6677c67869cf41f2a23af991a8920051,

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.",

author = "Ping-Pui Wong and Mu{\~n}oz-F{\'e}lix, {Jos{\'e} M} and Maruan Hijazi and Hyojin Kim and Robinson, {Stephen D} and {De Lux{\'a}n-Delgado}, Beatriz and Irene Rodr{\'i}guez-Hern{\'a}ndez 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 Henderson, {Neil C} and Szlosarek, {Peter W} and Dreger, {Sally A} and Sally Smith and Jones, {J Louise} and Gribben, {John G} and Cutillas, {Pedro R} and Pascal Meier and Victoria Sanz-Moreno and Hodivala-Dilke, {Kairbaan M}",

year = "2020",

month = jun,

day = "11",

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

language = "English",

volume = "181",

pages = "1346--1363.e21",

journal = "Cell",

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publisher = "Elsevier",

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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 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

T1 - Cancer Burden Is Controlled by Mural Cell-β3-Integrin Regulated Crosstalk with Tumor Cells

AU - Wong, Ping-Pui

AU - Muñoz-Félix, José M

AU - Hijazi, Maruan

AU - Kim, Hyojin

AU - Robinson, Stephen D

AU - De Luxán-Delgado, Beatriz

AU - Rodríguez-Hernández, 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 C

AU - Szlosarek, Peter W

AU - Dreger, Sally A

AU - Smith, Sally

AU - Jones, J Louise

AU - Gribben, John G

AU - Cutillas, Pedro R

AU - Meier, Pascal

AU - Sanz-Moreno, Victoria

AU - Hodivala-Dilke, Kairbaan M

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.

U2 - 10.1016/j.cell.2020.02.003

DO - 10.1016/j.cell.2020.02.003

M3 - Article

C2 - 32473126

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

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