Yihai Cao Group

Yihai Cao 2018

General Research Description

Our research program focuses on studying the fundamental mechanisms of angiogenesis, the key process of blood vessel formation, in various diseases. Our aim is to understand molecular and functional mechanisms of angiogenesis in the onset and progression of most common and lethal human diseases such as cancer, metabolic disease, and cardiovascular disease. Through these mechanistic studies, we propose new concepts and paradigms that are beneficial for diagnosis, treatment, and prevention of these and other human diseases. The ultimate goal of our research is to develop novel therapeutics for treatment of angiogenesis-dependent diseases.

Cancer and Metastasis

Yihai Cao illustration from publication in Science 2010In the cancer front, we are actively studying the mechanisms underlying invasion, metastasis, and drug responses.  In particular, we study the interaction between tumor vessels and other cellular components in the tumor microenvironment for promoting cancer spreading and drug resistance. Our groundbreaking discoveries have provided new clues for effective treatment of various cancers by targeting the tumor vasculature. Our research project is translational in nature and clinically meaningful. We aim to improve the therapeutic efficacy of antiangiogenic drugs either alone or in combination with other therapeutic modalities. We have provided new mechanistic insights and rationales for antiangiogenic combination therapy with other therapeutics, improvement of antiangiogenic drug resistance, optimal timeline of therapy, mechanisms of action, and minimizing adverse effects (Figure 1). We have also discovered several novel mechanisms that underlie cancer metastasis.  Recently, we have found that other cellular components including CAFs and TAMs mediate cancer metastasis through interacting with tumor vessels. In addition to blood stream metastasis, we have uncovered new mechanisms by which cancer cell spread through the lymphatic system. Lymphangiogenesis is an emerging interesting field and we are actively studying its role in cancer metastasis.

Obesisty and Metabolic Diseases

In the obesity and metabolic disease research front, we were one of the first in the world proposing the modulation of adipose vasculature for treating obesity, diabetes and other metabolic diseases. We have identified several novel molecular players that mediate the crosstalk between the vasculature and adipocytes.  Using physiological cold exposure as an experimental tool, we have found that angiogenic vessels are Vascular functions in adiposecrucial for controlling the metabolic status of adipocytes (Figure2 left: Vascular functions in adipose)  Augmenting adipose angiogenesis can switch the white fat to become brown-like fat (browning fat).  Moreover, we are able to make the most harmful visceral white fat to be metabolically beneficial browning fat, which helps to dissipate energy, leading to improvement of insulin sensitivity and metabolic dysfunctions in obese animals. We discovered novel mechanisms of vascular autocrine, paracrine and endocrine regulatory mechanisms for regulation of adipose tissue functions. Targeting angiogenesis has become a very exciting approach for treatment of obesity, diabetes, other metabolic diseases, their complications (Figure 3). We continue to work and lead this interesting research area.  WE strongly believe that our findings will pave new avenues for developing novel therapeutics for treatment of obesity, diabetes and their complications.

Angiogenesis and other diseases

Our other research programs include therapeutic angiogenesis for treating cardiovascular disease, especially after myocardial infarction.  We have developed a novel regimen of combination therapy targeting both angiogenesis and arteriogenesis. We have also developed novel therapeutics that target vasculatures, fibrosis, and inflammation for treating eye diseases including age-related macular disease (AMD) and glaucoma.. These novel therapeutics are ready for early clinical trials and preclinical studies demonstrated exciting therapeutic efficacy.

Targeting angiogenesis for the treatment of obesisty, diabetes and other metabolic diseases

Yihai Cao interdisciplinary researchIn our research, we employ interdisciplinary experimental approaches to tackle clinically relevant unmet medical problems. We have created an exciting international environment for young scientists with different nationalities to work together. We welcome talented young scientists, postdoctoral fellows, Ph.D. students, and visiting scientists to join our team to work on these exciting research programs.

 

Selected Publications

Ablation of endothelial VEGFR1 improves metabolic dysfunction by inducing adipose tissue browning.
Seki T, Hosaka K, Fischer C, Lim S, Andersson P, Abe M, et al
J. Exp. Med. 2018 Feb;215(2):611-626

A miR-327-FGF10-FGFR2-mediated autocrine signaling mechanism controls white fat browning.
Fischer C, Seki T, Lim S, Nakamura M, Andersson P, Yang Y, et al
Nat Commun 2017 Dec;8(1):2079

Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism.
Yang Y, Zhang Y, Iwamoto H, Hosaka K, Seki T, Andersson P, et al
Nat Commun 2016 Sep;7():12680

Endothelial PDGF-CC regulates angiogenesis-dependent thermogenesis in beige fat.
Seki T, Hosaka K, Lim S, Fischer C, Honek J, Yang Y, et al
Nat Commun 2016 Aug;7():12152

The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages.
Yang Y, Andersson P, Hosaka K, Zhang Y, Cao R, Iwamoto H, et al
Nat Commun 2016 05;7():11385

MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis.
Wong H, Jin G, Cao R, Zhang S, Cao Y, Zhou Z
Nat Commun 2016 Mar;7():10824

PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors.
Iwamoto H, Zhang Y, Seki T, Yang Y, Nakamura M, Wang J, et al
Sci Adv 2015 Apr;1(3):e1400244

TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling.
Ji H, Cao R, Yang Y, Zhang Y, Iwamoto H, Lim S, et al
Nat Commun 2014 Sep;5():4944

Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity.
Cao Y
Cell Metab. 2013 Oct;18(4):478-89

Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis.
Hosaka K, Yang Y, Seki T, Nakamura M, Andersson P, Rouhi P, et al
Nat Commun 2013 ;4():2129

Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay.
Martinez Molina D, Jafari R, Ignatushchenko M, Seki T, Larsson E, Dan C, et al
Science 2013 Jul;341(6141):84-7

Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis.
Dong M, Yang X, Lim S, Cao Z, Honek J, Lu H, et al
Cell Metab. 2013 Jul;18(1):118-29

All Publications

2018

Obesity Protects Cancer from Drugs Targeting Blood Vessels.
Cao Y
Cell Metab. 2018 Jun;27(6):1163-1165

A novel mechanism of the M1-M2 methionine adenosyltransferase switch-mediated hepatocellular carcinoma metastasis.
Wang R, Jin Y, Yao X, Fan W, Zhang J, Cao Y, et al
Mol. Carcinog. 2018 May;():

CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis.
Guo L, Akahori H, Harari E, Smith S, Polavarapu R, Karmali V, et al
J. Clin. Invest. 2018 Mar;128(3):1106-1124

Dual roles of endothelial FGF-2-FGFR1-PDGF-BB and perivascular FGF-2-FGFR2-PDGFRβ signaling pathways in tumor vascular remodeling.
Hosaka K, Yang Y, Nakamura M, Andersson P, Yang X, Zhang Y, et al
Cell Discov 2018 ;4():3

Ablation of endothelial VEGFR1 improves metabolic dysfunction by inducing adipose tissue browning.
Seki T, Hosaka K, Fischer C, Lim S, Andersson P, Abe M, et al
J. Exp. Med. 2018 Feb;215(2):611-626

Novel concept of the smart NIR-light-controlled drug release of black phosphorus nanostructure for cancer therapy.
Qiu M, Wang D, Liang W, Liu L, Zhang Y, Chen X, et al
Proc. Natl. Acad. Sci. U.S.A. 2018 Jan;115(3):501-506

2017

A miR-327-FGF10-FGFR2-mediated autocrine signaling mechanism controls white fat browning.
Fischer C, Seki T, Lim S, Nakamura M, Andersson P, Yang Y, et al
Nat Commun 2017 Dec;8(1):2079

Novel concept of the smart NIR-light-controlled drug release of black phosphorus nanostructure for cancer therapy.
Qiu M, Wang D, Liang W, Liu L, Zhang Y, Chen X, et al
Proc. Natl. Acad. Sci. U.S.A. 2018 Jan;115(3):501-506

Off-tumor targets compromise antiangiogenic drug sensitivity by inducing kidney erythropoietin production.
Nakamura M, Zhang Y, Yang Y, Sonmez C, Zheng W, Huang G, et al
Proc. Natl. Acad. Sci. U.S.A. 2017 11;114(45):E9635-E9644

Critical role of caveolin-1 in ocular neovascularization and multitargeted antiangiogenic effects of cavtratin via JNK.
Jiang Y, Lin X, Tang Z, Lee C, Tian G, Du Y, et al
Proc. Natl. Acad. Sci. U.S.A. 2017 10;114(40):10737-10742

MicroRNA-26a and -26b inhibit lens fibrosis and cataract by negatively regulating Jagged-1/Notch signaling pathway.
Chen X, Xiao W, Chen W, Liu X, Wu M, Bo Q, et al
Cell Death Differ. 2017 08;24(8):1431-1442

Maintenance of antiangiogenic and antitumor effects by orally active low-dose capecitabine for long-term cancer therapy.
Zhang Y, Sun M, Huang G, Yin L, Lai Q, Yang Y, et al
Proc. Natl. Acad. Sci. U.S.A. 2017 06;114(26):E5226-E5235

A Zebrafish Model Discovers a Novel Mechanism of Stromal Fibroblast-Mediated Cancer Metastasis.
Liu C, Zhang Y, Lim S, Hosaka K, Yang Y, Pavlova T, et al
Clin. Cancer Res. 2017 Aug;23(16):4769-4779

Switching harmful visceral fat to beneficial energy combustion improves metabolic dysfunctions.
Yang X, Sui W, Zhang M, Dong M, Lim S, Seki T, et al
JCI Insight 2017 Feb;2(4):e89044

2016

Residential Proximity to Major Roadways and Risk of Type 2 Diabetes Mellitus: A Meta-Analysis.
Zhao Z, Lin F, Wang B, Cao Y, Hou X, Wang Y
Int J Environ Res Public Health 2016 12;14(1):

Pericyte-fibroblast transition promotes tumor growth and metastasis.
Hosaka K, Yang Y, Seki T, Fischer C, Dubey O, Fredlund E, et al
Proc. Natl. Acad. Sci. U.S.A. 2016 09;113(38):E5618-27

Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism.
Yang Y, Zhang Y, Iwamoto H, Hosaka K, Seki T, Andersson P, et al
Nat Commun 2016 Sep;7():12680

Endothelial PDGF-CC regulates angiogenesis-dependent thermogenesis in beige fat.
Seki T, Hosaka K, Lim S, Fischer C, Honek J, Yang Y, et al
Nat Commun 2016 Aug;7():12152

Estrogen Receptor α Promotes Breast Cancer by Reprogramming Choline Metabolism.
Jia M, Andreassen T, Jensen L, Bathen T, Sinha I, Gao H, et al
Cancer Res. 2016 10;76(19):5634-5646

Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis.
Lim S, Hosaka K, Nakamura M, Cao Y
Oncotarget 2016 Jun;7(25):38282-38291

The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages.
Yang Y, Andersson P, Hosaka K, Zhang Y, Cao R, Iwamoto H, et al
Nat Commun 2016 05;7():11385

Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy.
Zhang Y, Yang Y, Hosaka K, Huang G, Zang J, Chen F, et al
Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113(15):4158-63

Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE.
Carmona G, Perera U, Gillett C, Naba A, Law A, Sharma V, et al
Oncogene 2016 09;35(39):5155-69

MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis.
Wong H, Jin G, Cao R, Zhang S, Cao Y, Zhou Z
Nat Commun 2016 Mar;7():10824

Future options of anti-angiogenic cancer therapy.
Cao Y
Chin J Cancer 2016 Feb;35():21

Resveratrol analogue 4,4'-dihydroxy-trans-stilbene potently inhibits cancer invasion and metastasis.
Savio M, Ferraro D, Maccario C, Vaccarone R, Jensen L, Corana F, et al
Sci Rep 2016 Feb;6():19973

2015

VEGF-B-Neuropilin-1 signaling is spatiotemporally indispensable for vascular and neuronal development in zebrafish.
Jensen L, Nakamura M, Bräutigam L, Li X, Liu Y, Samani N, et al
Proc. Natl. Acad. Sci. U.S.A. 2015 Nov;112(44):E5944-53

Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain.
Hameed L, Berg D, Belnoue L, Jensen L, Cao Y, Simon A
Elife 2015 Oct;4():

Invasiveness and metastasis of retinoblastoma in an orthotopic zebrafish tumor model.
Chen X, Wang J, Cao Z, Hosaka K, Jensen L, Yang H, et al
Sci Rep 2015 Jul;5():10351

VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism and serves as a marker of poor prognosis for cancer patients.
Yang X, Zhang Y, Hosaka K, Andersson P, Wang J, Tholander F, et al
Proc. Natl. Acad. Sci. U.S.A. 2015 Jun;112(22):E2900-9

CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer.
Svensson S, Abrahamsson A, Rodriguez G, Olsson A, Jensen L, Cao Y, et al
Clin. Cancer Res. 2015 Aug;21(16):3794-805

PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors.  Hideki Iwamoto, Yin Zhang, Takahiro Seki, Yunlong Yang, Masaki Nakamura, Jian Wang, Xiaojuan Yang, Takuji Torimura, Yihai Cao. Science Advances 10 Apr 2015: Vol. 1 no. 3 e1400244 DOI: 10.1126/sciadv.1400244

2014

MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes.
Keklikoglou I, Hosaka K, Bender C, Bott A, Koerner C, Mitra D, et al
Oncogene 2015 Sep;34(37):4867-78

Hypoxic regulation of RIOK3 is a major mechanism for cancer cell invasion and metastasis.
Singleton D, Rouhi P, Zois C, Haider S, Li J, Kessler B, et al
Oncogene 2015 Sep;34(36):4713-22

Novel mechanism of macrophage-mediated metastasis revealed in a zebrafish model of tumor development.
Wang J, Cao Z, Zhang X, Nakamura M, Sun M, Hartman J, et al
Cancer Res. 2015 Jan;75(2):306-15

VEGFR2-mediated vascular dilation as a mechanism of VEGF-induced anemia and bone marrow cell mobilization.
Lim S, Zhang Y, Zhang D, Chen F, Hosaka K, Feng N, et al
Cell Rep 2014 Oct;9(2):569-80

Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues.
Honek J, Seki T, Iwamoto H, Fischer C, Li J, Lim S, et al
Proc. Natl. Acad. Sci. U.S.A. 2014 Oct;111(41):14906-11

Vasoprotective effect of PDGF-CC mediated by HMOX1 rescues retinal degeneration.
He C, Zhao C, Kumar A, Lee C, Chen M, Huang L, et al
Proc. Natl. Acad. Sci. U.S.A. 2014 Oct;111(41):14806-11

TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling.
Ji H, Cao R, Yang Y, Zhang Y, Iwamoto H, Lim S, et al
Nat Commun 2014 Sep;5():4944

VEGF-targeted cancer therapeutics-paradoxical effects in endocrine organs.
Cao Y
Nat Rev Endocrinol 2014 Sep;10(9):530-9

Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer.
Zhao C, Qiao Y, Jonsson P, Wang J, Xu L, Rouhi P, et al
Cancer Res. 2014 Jul;74(14):3983-94

Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response.
Zheng X, Zhou A, Rouhi P, Uramoto H, Borén J, Cao Y, et al
Proc. Natl. Acad. Sci. U.S.A. 2014 Feb;111(7):2560-5

Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis.
Arjonen A, Kaukonen R, Mattila E, Rouhi P, Högnäs G, Sihto H, et al
J. Clin. Invest. 2014 Mar;124(3):1069-82

Older Publications

Link to all Yihai Cao Publications on PubMed

 

Group Members

Professor

Yihai Cao

Phone: +46-(0)8-524 875 96
Organizational unit: Yihai Cao group
E-mail: Yihai.Cao@ki.se

Associated

xiaoting sun

E-mail: xiaoting.sun@ki.se

Associated

André Dias

Phone: 852486299
E-mail: andre.dias@ki.se

Graduate Student

Jieyu Wu

Organizational unit: Department of Microbiology, Tumor and Cell Biology (MTC), C1
E-mail: jieyu.wu@ki.se

Associated

Xingkang He

E-mail: xingkang.he@ki.se

Patrik AnderssonPostdoc
Yihai CaoProfessor
Renhai CaoSenior researcher
Li ChenBiomedical scientist
Carina FischerPhD student, Graduate Student
Kayoko HosakaSenior lab manager
Huazheng PanAssociated
Takahiro SekiSenior lab manager
Jieyu WuGraduate Student

 

Former Members

Former Group Members

Links