Immune-mediated ECM depletion improves tumour perfusion and payload delivery

Yen Ling Yeow, Venkata Ramana Kotamraju, Xiao Wang, Meenu Chopra, Nasibah Azme, Jiansha Wu, Tobias D. Schoep, Derek S. Delaney, Kirk Feindel, Ji Li, Kelsey M. Kennedy, Wes M. Allen, Brendan F. Kennedy, Irma Larma, David D. Sampson, Lisa M. Mahakian, Brett Z. Fite, Hua Zhang, Tomas Friman, Aman P. Mann & 11 others Farah A. Aziz, M. Priyanthi Kumarasinghe, Mikael Johansson, Hooi C. Ee, George Yeoh, Lingjun Mou, Katherine W. Ferrara, Hector Billiran, Ruth Ganss, Erkki Ruoslahti, Juliana Hamzah

Research output: Contribution to journalArticle

Abstract

High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin–nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα.

Original languageEnglish
Article numbere10923
JournalEMBO Molecular Medicine
DOIs
Publication statusE-pub ahead of print - 11 Nov 2019

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Extracellular Matrix
Perfusion
Neoplasms
Tumor Necrosis Factor-alpha
Peptides
Vascular Tissue Neoplasms
Poisons
Nanoparticles
Contrast Media
Dilatation
Cytokines
Ligands
Carcinoma
Growth

Cite this

Yeow, Yen Ling ; Kotamraju, Venkata Ramana ; Wang, Xiao ; Chopra, Meenu ; Azme, Nasibah ; Wu, Jiansha ; Schoep, Tobias D. ; Delaney, Derek S. ; Feindel, Kirk ; Li, Ji ; Kennedy, Kelsey M. ; Allen, Wes M. ; Kennedy, Brendan F. ; Larma, Irma ; Sampson, David D. ; Mahakian, Lisa M. ; Fite, Brett Z. ; Zhang, Hua ; Friman, Tomas ; Mann, Aman P. ; Aziz, Farah A. ; Kumarasinghe, M. Priyanthi ; Johansson, Mikael ; Ee, Hooi C. ; Yeoh, George ; Mou, Lingjun ; Ferrara, Katherine W. ; Billiran, Hector ; Ganss, Ruth ; Ruoslahti, Erkki ; Hamzah, Juliana. / Immune-mediated ECM depletion improves tumour perfusion and payload delivery. In: EMBO Molecular Medicine. 2019.
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abstract = "High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin–nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα.",
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author = "Yeow, {Yen Ling} and Kotamraju, {Venkata Ramana} and Xiao Wang and Meenu Chopra and Nasibah Azme and Jiansha Wu and Schoep, {Tobias D.} and Delaney, {Derek S.} and Kirk Feindel and Ji Li and Kennedy, {Kelsey M.} and Allen, {Wes M.} and Kennedy, {Brendan F.} and Irma Larma and Sampson, {David D.} and Mahakian, {Lisa M.} and Fite, {Brett Z.} and Hua Zhang and Tomas Friman and Mann, {Aman P.} and Aziz, {Farah A.} and Kumarasinghe, {M. Priyanthi} and Mikael Johansson and Ee, {Hooi C.} and George Yeoh and Lingjun Mou and Ferrara, {Katherine W.} and Hector Billiran and Ruth Ganss and Erkki Ruoslahti and Juliana Hamzah",
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Yeow, YL, Kotamraju, VR, Wang, X, Chopra, M, Azme, N, Wu, J, Schoep, TD, Delaney, DS, Feindel, K, Li, J, Kennedy, KM, Allen, WM, Kennedy, BF, Larma, I, Sampson, DD, Mahakian, LM, Fite, BZ, Zhang, H, Friman, T, Mann, AP, Aziz, FA, Kumarasinghe, MP, Johansson, M, Ee, HC, Yeoh, G, Mou, L, Ferrara, KW, Billiran, H, Ganss, R, Ruoslahti, E & Hamzah, J 2019, 'Immune-mediated ECM depletion improves tumour perfusion and payload delivery' EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201910923

Immune-mediated ECM depletion improves tumour perfusion and payload delivery. / Yeow, Yen Ling; Kotamraju, Venkata Ramana; Wang, Xiao; Chopra, Meenu; Azme, Nasibah; Wu, Jiansha; Schoep, Tobias D.; Delaney, Derek S.; Feindel, Kirk; Li, Ji; Kennedy, Kelsey M.; Allen, Wes M.; Kennedy, Brendan F.; Larma, Irma; Sampson, David D.; Mahakian, Lisa M.; Fite, Brett Z.; Zhang, Hua; Friman, Tomas; Mann, Aman P.; Aziz, Farah A.; Kumarasinghe, M. Priyanthi; Johansson, Mikael; Ee, Hooi C.; Yeoh, George; Mou, Lingjun; Ferrara, Katherine W.; Billiran, Hector; Ganss, Ruth; Ruoslahti, Erkki; Hamzah, Juliana.

In: EMBO Molecular Medicine, 11.11.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Immune-mediated ECM depletion improves tumour perfusion and payload delivery

AU - Yeow, Yen Ling

AU - Kotamraju, Venkata Ramana

AU - Wang, Xiao

AU - Chopra, Meenu

AU - Azme, Nasibah

AU - Wu, Jiansha

AU - Schoep, Tobias D.

AU - Delaney, Derek S.

AU - Feindel, Kirk

AU - Li, Ji

AU - Kennedy, Kelsey M.

AU - Allen, Wes M.

AU - Kennedy, Brendan F.

AU - Larma, Irma

AU - Sampson, David D.

AU - Mahakian, Lisa M.

AU - Fite, Brett Z.

AU - Zhang, Hua

AU - Friman, Tomas

AU - Mann, Aman P.

AU - Aziz, Farah A.

AU - Kumarasinghe, M. Priyanthi

AU - Johansson, Mikael

AU - Ee, Hooi C.

AU - Yeoh, George

AU - Mou, Lingjun

AU - Ferrara, Katherine W.

AU - Billiran, Hector

AU - Ganss, Ruth

AU - Ruoslahti, Erkki

AU - Hamzah, Juliana

PY - 2019/11/11

Y1 - 2019/11/11

N2 - High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin–nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα.

AB - High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin–nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα.

KW - extracellular matrix

KW - immune cells

KW - peptide

KW - solid tumour

KW - tumour necrosis factor alpha

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U2 - 10.15252/emmm.201910923

DO - 10.15252/emmm.201910923

M3 - Article

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

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