Endothelial p130cas confers resistance to anti-angiogenesis therapy

Yunfei Wen; Anca Chelariu-Raicu; Sujanitha Umamaheswaran; Alpa M. Nick; Elaine Stur; Pahul Hanjra; Dahai Jiang; Nicholas B. Jennings; Xiuhui Chen; Sara Corvigno; Deanna Glassman; Gabriel Lopez-Berestein; Jinsong Liu; Mien Chie Hung; Anil K. Sood

doi:10.1016/j.celrep.2022.110301

Endothelial p130cas confers resistance to anti-angiogenesis therapy

Yunfei Wen, Anca Chelariu-Raicu, Sujanitha Umamaheswaran, Alpa M. Nick, Elaine Stur, Pahul Hanjra, Dahai Jiang, Nicholas B. Jennings, Xiuhui Chen, Sara Corvigno, Deanna Glassman, Gabriel Lopez-Berestein, Jinsong Liu, Mien Chie Hung, Anil K. Sood

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

4 Scopus citations

Abstract

Anti-angiogenic therapies, such as anti-VEGF antibodies (AVAs), have shown promise in clinical settings. However, adaptive resistance to such therapies occurs frequently. We use orthotopic ovarian cancer models with AVA-adaptive resistance to investigate the underlying mechanisms. Genomic profiling of AVA-resistant tumors guides us to endothelial p130cas. We find that bevacizumab induces cleavage of VEGFR2 in endothelial cells by caspase-10 and that VEGFR2 fragments internalize into the nucleus and autophagosomes. Nuclear VEGFR2 and p130cas fragments, together with TNKS1BP1 (tankyrase-1-binding protein), initiate endothelial cell death. Blockade of autophagy in AVA-resistant endothelial cells retains VEGFR2 at the membrane with bevacizumab treatment. Targeting host p130cas with RGD (Arg-Gly-Asp)-tagged nanoparticles or genomic ablation of vascular p130cas in p130cas^flox/floxTie2^Cre mice significantly extends the survival of mice with AVA-resistant ovarian tumors. Higher vascular p130cas is associated with shorter survival of individuals with ovarian cancer. Our findings identify opportunities for new strategies to overcome adaptive resistance to AVA therapy.

Original language	English (US)
Article number	110301
Journal	Cell Reports
Volume	38
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2022.110301
State	Published - Jan 25 2022

Keywords

TNKS1BP1
VEGFR2
adaptive resistance
angiogenesis
anti-angiogenic therapy
autophagy
p130cas

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

Research Animal Support Facility
Genetically Engineered Mouse Facility
Flow Cytometry and Cellular Imaging Facility

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10.1016/j.celrep.2022.110301

Cite this

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title = "Endothelial p130cas confers resistance to anti-angiogenesis therapy",

abstract = "Anti-angiogenic therapies, such as anti-VEGF antibodies (AVAs), have shown promise in clinical settings. However, adaptive resistance to such therapies occurs frequently. We use orthotopic ovarian cancer models with AVA-adaptive resistance to investigate the underlying mechanisms. Genomic profiling of AVA-resistant tumors guides us to endothelial p130cas. We find that bevacizumab induces cleavage of VEGFR2 in endothelial cells by caspase-10 and that VEGFR2 fragments internalize into the nucleus and autophagosomes. Nuclear VEGFR2 and p130cas fragments, together with TNKS1BP1 (tankyrase-1-binding protein), initiate endothelial cell death. Blockade of autophagy in AVA-resistant endothelial cells retains VEGFR2 at the membrane with bevacizumab treatment. Targeting host p130cas with RGD (Arg-Gly-Asp)-tagged nanoparticles or genomic ablation of vascular p130cas in p130casflox/floxTie2Cre mice significantly extends the survival of mice with AVA-resistant ovarian tumors. Higher vascular p130cas is associated with shorter survival of individuals with ovarian cancer. Our findings identify opportunities for new strategies to overcome adaptive resistance to AVA therapy.",

keywords = "TNKS1BP1, VEGFR2, adaptive resistance, angiogenesis, anti-angiogenic therapy, autophagy, p130cas",

author = "Yunfei Wen and Anca Chelariu-Raicu and Sujanitha Umamaheswaran and Nick, {Alpa M.} and Elaine Stur and Pahul Hanjra and Dahai Jiang and Jennings, {Nicholas B.} and Xiuhui Chen and Sara Corvigno and Deanna Glassman and Gabriel Lopez-Berestein and Jinsong Liu and Hung, {Mien Chie} and Sood, {Anil K.}",

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year = "2022",

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doi = "10.1016/j.celrep.2022.110301",

language = "English (US)",

volume = "38",

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T1 - Endothelial p130cas confers resistance to anti-angiogenesis therapy

AU - Wen, Yunfei

AU - Chelariu-Raicu, Anca

AU - Umamaheswaran, Sujanitha

AU - Nick, Alpa M.

AU - Stur, Elaine

AU - Hanjra, Pahul

AU - Jiang, Dahai

AU - Jennings, Nicholas B.

AU - Chen, Xiuhui

AU - Corvigno, Sara

AU - Glassman, Deanna

AU - Lopez-Berestein, Gabriel

AU - Liu, Jinsong

AU - Hung, Mien Chie

AU - Sood, Anil K.

PY - 2022/1/25

Y1 - 2022/1/25

N2 - Anti-angiogenic therapies, such as anti-VEGF antibodies (AVAs), have shown promise in clinical settings. However, adaptive resistance to such therapies occurs frequently. We use orthotopic ovarian cancer models with AVA-adaptive resistance to investigate the underlying mechanisms. Genomic profiling of AVA-resistant tumors guides us to endothelial p130cas. We find that bevacizumab induces cleavage of VEGFR2 in endothelial cells by caspase-10 and that VEGFR2 fragments internalize into the nucleus and autophagosomes. Nuclear VEGFR2 and p130cas fragments, together with TNKS1BP1 (tankyrase-1-binding protein), initiate endothelial cell death. Blockade of autophagy in AVA-resistant endothelial cells retains VEGFR2 at the membrane with bevacizumab treatment. Targeting host p130cas with RGD (Arg-Gly-Asp)-tagged nanoparticles or genomic ablation of vascular p130cas in p130casflox/floxTie2Cre mice significantly extends the survival of mice with AVA-resistant ovarian tumors. Higher vascular p130cas is associated with shorter survival of individuals with ovarian cancer. Our findings identify opportunities for new strategies to overcome adaptive resistance to AVA therapy.

AB - Anti-angiogenic therapies, such as anti-VEGF antibodies (AVAs), have shown promise in clinical settings. However, adaptive resistance to such therapies occurs frequently. We use orthotopic ovarian cancer models with AVA-adaptive resistance to investigate the underlying mechanisms. Genomic profiling of AVA-resistant tumors guides us to endothelial p130cas. We find that bevacizumab induces cleavage of VEGFR2 in endothelial cells by caspase-10 and that VEGFR2 fragments internalize into the nucleus and autophagosomes. Nuclear VEGFR2 and p130cas fragments, together with TNKS1BP1 (tankyrase-1-binding protein), initiate endothelial cell death. Blockade of autophagy in AVA-resistant endothelial cells retains VEGFR2 at the membrane with bevacizumab treatment. Targeting host p130cas with RGD (Arg-Gly-Asp)-tagged nanoparticles or genomic ablation of vascular p130cas in p130casflox/floxTie2Cre mice significantly extends the survival of mice with AVA-resistant ovarian tumors. Higher vascular p130cas is associated with shorter survival of individuals with ovarian cancer. Our findings identify opportunities for new strategies to overcome adaptive resistance to AVA therapy.

KW - TNKS1BP1

KW - VEGFR2

KW - adaptive resistance

KW - angiogenesis

KW - anti-angiogenic therapy

KW - autophagy

KW - p130cas

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Endothelial p130cas confers resistance to anti-angiogenesis therapy

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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