Headerlogotextwithshieldsshadowed
Dai Fukumura
Associate Prof., Radiation Oncology

Fukumura Lab Research

Angiogenesis and Microcirculation in Physiological and Pathophysiological Settings

The long-term goal of my research is to uncover the fundamental nature of vascular biology in both physiological and pathophysiological settings, and to utilize this knowledge for detection and treatment of diseases. Together with outstanding collaborators, I have been developing and utilizing state of the art imaging techniques and animal models which led to the discoveries summarize below.

Role of NO in tumor angiogenesis, lymphangiogenesis, microcirculation and radiation therapy

Nitric oxide (NO) is a highly reactive mediator with a variety of physiological and pathological functions. NO increases and/or maintains tumor blood flow, decreases leukocyte-endothelial interactions, and increases vascular permeability and thus, may facilitate tumor growth. Furthermore, NO mediates angiogenesis and vessel maturation predominantly through endothelial NO synthase. We also found that NO mediates lymph-angiogenesis and metastasis as well as function of lymphatic vessels. We recently uncovered that restoration of perivascular NO gradients improves structure and function of both blood and lymphatic vessels, and response to radiation.

Role of tumor-host interactions in angiogenesis, tumor growth and metastasis

Using genetically engineered mouse and tumor models as well as in vivo imaging techniques, we found for the first time that nontransformed stromal cells –including activated fibroblasts, bone marrow derived cells – are a major inducer of tumor angiogenesis and mediate the formation of abnormal microenvironment. Furthermore, various anti-angiogenic or molecularly targeting treatments result in the activation of host stromal cells leading to treatment resistance. Our recent data indicate that stromal cells in the primary tumor travel with tumor cells and facilitate survival and growth of metastatic tumors. Controlling tumor-host interaction is an promising approach to facilitate tumor treatment. For example,, the blockade of vascular endothelial growth factor signaling can transiently normalize tumor vasculature and potentiate anti-tumor cytotoxic therapies.

Probing tumor microenvironment using nanotechnology

We have been studying the tumor microenvironment and transport properties using nano-probes. We found that relatively large nanoparticles – size of current nanomedicine – can take advantage of enhanced permeability and retention effect for transvascular transport but are unable to penetrate into tumor tissues. We also found superior transvascular transport of rod-shape over spherical nanoparticles. Furthermore, we discovered that neutral charge is the best for interstitial transport. These findings led us to develop multistage nanotherapeutics that shrink upon the entry to the tumor microenvironment in order to facilitate interstitial transport.

Role of obesity in angiogenesis, tumor growth and treatments.

First, we established in vivo system to investigate blood vessel formation during adipogenesis. Using genetic inhibition of PPAR? and pharmacological inhibition of VEGFR2 signaling we found provocative reciprocal regulation of adipogenesis and angiogenesis, suggesting a novel strategy to treat obesity related diseases including cancer. We then established a physiologically based mathematical model and found that leptin pathway plays a key role in maintenance of body mass and its disruption destroys the body weight balance. We are currently studying the underling mechanisms of obesity-induced aggravation of breast cancer through both preclinical studies and clinical trials of breast cancer patients.

Engineering blood vessels

A major limitation of tissue engineering is the lack of functional blood and lymph vessels. First, we established a model to monitor tissue engineered blood vessels in vivo using MPLSM. We found that mesenchymal precursor cells accelerate remodeling of 3-D endothelial cell structure to functional blood vessels, differentiate into peri-vascular cells, and stabilize engineered vessel network for up to a year. Using this tissue engineered blood vessel model,.we then, showed that human ES cell, cord blood and peripheral blood -derived endothelial cells form functional blood vessels in vivo and that human bone marrow derived mesenchymal stem cells serve as perivascular precursor cells, mature and stabilize blood vessels. Detail observation of vessel anastomosis in these tissue-engineered blood vessels revealed a novel mechanism – wrapping-and-tapping of host vessels. More recently, we have established robust protocols deriving endothelial cells and mesenchymal precursor cells from induced pluripotent stem (iPS) cells and successfully generated blood vessels these iPS-derived cells

Lab News

Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2


Immunosuppression underlies resistance to anti-angiogenic therapy

“Deciphering and targeting mechanisms involved in resistance to anti-angiogenic therapy is critical to realizing the full potential of this promising cancer therapy,” says Dai Fukumura, MD, PhD, deputy director of the Steele Labs, co-senior author of the paper. “Not only is this the first report investigating the role in anti-angiogenic cancer therapy of a subset of innate immune cells – Ly6Clowor non-classical monocytes – it is also the first to find an immunosuppressive function for these cells and to identify that as the key mechanism conferring resistance to anti-angiogenic therapy.” 

Dr. Dai Fukumura Elected to 2017 AIMBE Class of the College of Fellows
Congratulations to Dr. Dai Fukumura for being elected to the American Institute for Medical and Biological Engineering (AIMBE) 2017 Class of the College of Fellows! Dr. Fukumura will be inducted during AIMBE's 2017 Annual Event, March 19-20, 2017, in Washington D.C.
Steele Labs researchers discover potential mechanism of resistance to antiangiogenic treatment in cancer
Researchers in the Edwin L. Steele Laboratories have discovered a new mechanism of resistance that may explain why antiangiogenic therapy has failed in some cancers. In a paper recently published in and featured on the cover of Science Translational Medicine, researchers found that treating metastatic colorectal cancer with Avastin (an anti-VEGF agent) significantly increases extracellular matrix components and stiffness in colorectal cancer liver metastases from patients and mouse models. Not only did antiangiogenic therapy lead to an increase in matrix molecules such as hyaluronan and sulfated glycosaminoglycans - contributing to increased compressive forces and tissue stiffness in liver metastases - but it also caused an influx of immune suppressor cells that would contribute to poor response. The preclinical and clinical findings featured in this study will offer new insights into how treatment resistance arises, and suggest new methods to overcome it. Check out the press release from MGH here, coverage of this article in Cancer Discovery Research Watch, and click on the following links to the Science Translational Medicine website for the abstract, reprint, and full text of the article.
Steele labs research team finds how obesity contributes to and blocks treatment of pancreatic cancer
Researchers in the Edwin L. Steele Laboratories have discovered a new mechanism by which obesity increases inflammation and connective tissue in pancreatic ductal adenocarcinoma. In their Cancer Discovery study, they found that interactions between fat, immune, and connective tissue cells in obesity contribute to tumor progression and chemotherapeutic resistance. By blocking the angiotensin II type-1 receptor signaling pathway, they were able to suppress the tumor-promoting microenvironment. Check out the press release from MGH, here and an interview with MedicalResearch.com here

Current Research

The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation.

Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, we observed increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival. These data provide a mechanistic basis for therapeutic resistance in the brain microenvironment and identify translatable treatment strategies for HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases.

Sci Transl Med. 2017;9(391):ePub - PMID: 28539475 - PMCID: PMC5917603 - DOI: 10.1126/scitranslmed.aal4682

It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacological inhibition of angiotensin-II type-1 receptor (AT1) reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSCs) in obesity is induced by tumor-associated neutrophils (TANs) recruited by adipocyte-secreted IL-1ß. PSCs further secrete IL-1ß, and inactivation of PSCs reduces IL-1ß expression and TAN recruitment. Furthermore, depletion of TANs, IL-1ß inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In pancreatic cancer patients, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that crosstalk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity.

Cancer Discov. 2016;6(8):852-69 - PMID: 27246539 - PMCID: PMC4972679 - DOI: 10.1158/2159-8290.CD-15-1177

Solid stress and elastic energy as measures of tumour mechanopathology

Solid stress and tissue stiffness affect tumour growth, invasion, metastasis and treatment. Unlike stiffness, which can be precisely  mapped in tumours, the measurement of solid stresses is challenging. Here, we show that two-dimensional spatial mappings of solid stress and the resulting elastic energy in excised or in situ tumours with arbitrary shapes and wide size ranges can be obtained via three distinct and quantitative techniques that rely on the measurement of tissue displacement after disruption of the confining structures. Application of these methods in models of primary tumours and metastasis revealed that: (i) solid stress depends on both cancer cells and their microenvironment; (ii) solid stress increases with tumour size; and (iii) mechanical confinement by the surrounding tissue significantly contributes to intratumoural solid stress. Further study of the genesis and consequences of solid stress, facilitated by the engineering principles presented here, may lead to significant discoveries and new therapies.

Nat Biomed Eng. 2016;1:ePub - PMID: 28966873 - PMCID: PMC5621647 - DOI: 10.1038/s41551-016-0004

Fukumura Lab Careers

Postdoctoral Fellows

Investigator: Fukumura, Dai
Date Posted: 2013-03-05
Description
The Steele Laboratory is currently seeking postdoctoral applicants with expertise in nitric oxide, angiogenesis, vessel maturation, molecular biology, and/or intravital microscopy. The project requires a motivated, independent researcher to carry out a project aimed at understanding role of nitric oxide in tumor angiogenesis, microcirculation and radiation therapy.
Requirements
Applicants should send a CV, career statement and three letters of reference to:
Dai Fukumura, MD, PhD
Associate Professor
Massachusetts General Hospital & Harvard Medical School
100 Blossom Street, Cox Building 736, Boston, MA 02114
dai@steele.mgh.harvard.edu

Selected Publications (from total of 224)

Li W, Liu Y, Yang W, Han X, Li S, Liu H, Gerweck LE, Fukumura D, Loeffler JS, Yang BB, Jain RK, Huang P
MicroRNA-378 enhances radiation response in ectopic and orthotopic implantation models of glioblastoma.
J Neurooncol. 2017;136(1):63-71 - PMID: 29081036 - PMCID: PMC5922763 - DOI: 10.1007/s11060-017-2646-y
Askoxylakis V, Badeaux M, Roberge S, Batista A, Kirkpatrick N, Snuderl M, Amoozgar Z, Seano G, Ferraro GB, Chatterjee S, Xu L, Fukumura D, Duda DG, Jain RK
A cerebellar window for intravital imaging of normal and disease states in mice.
Nat Protoc. 2017;12(11):2251-2262 - PMID: 28981123 - PMCID: PMC5918134 - DOI: 10.1038/nprot.2017.101
Jung K, Heishi T, Incio J, Huang Y, Beech EY, Pinter M, Ho WW, Kawaguchi K, Rahbari NN, Chung E, Kim JK, Clark JW, Willett CG, Yun SH, Luster AD, Padera TP, Jain RK, Fukumura D
Targeting CXCR4-dependent immunosuppressive Ly6C(low) monocytes improves antiangiogenic therapy in colorectal cancer.
Proc Natl Acad Sci U S A. 2017;114(39):10455-10460 - PMID: 28900008 - PMCID: PMC5625928 - DOI: 10.1073/pnas.1710754114
David P. Kodack, Vasileios Askoxylakis, Gino B. Ferraro, Qing Sheng, Mark Badeaux, Shom Goel, Xiaolong Qi, Ram Shankaraiah, Z. Alexander Cao, Rakesh R. Ramjiawan, Divya Bezwada, Bhushankumar Patel, Yongchul Song, Carlotta Costa, Kamila Naxerova, Christina S. F. Wong, Jonas Kloepper, Rita Das, Angela Tam, Jantima Tanboon, Dan G. Duda, C. Ryan Miller, Marni B. Siegel, Carey K. Anders, Melinda Sanders, Monica V. Estrada, Robert Schlegel, Carlos L. Arteaga, Elena Brachtel, Alan Huang, Dai Fukumura, Jeffrey A. Engelman, Rakesh K. Jain
The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation
Science Translational Medicine. 2017;9(391):eaal4682
Rowlands CJ, Park D, Bruns OT, Piatkevich KD, Fukumura D, Jain RK, Bawendi MG, Boyden ES, So PT
Wide-field three-photon excitation in biological samples.
Light Sci Appl. 2017;6:e16255 - PMID: 29152380 - PMCID: PMC5687557 - DOI: 10.1038/lsa.2016.255
Kodack DP, Askoxylakis V, Ferraro GB, Sheng Q, Badeaux M, Goel S, Qi X, Shankaraiah R, Cao ZA, Ramjiawan RR, Bezwada D, Patel B, Song Y, Costa C, Naxerova K, Wong CSF, Kloepper J, Das R, Tam A, Tanboon J, Duda DG, Miller CR, Siegel MB, Anders CK, Sanders M, Estrada MV, Schlegel R, Arteaga CL, Brachtel E, Huang A, Fukumura D, Engelman JA, Jain RK
The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation.
Sci Transl Med. 2017;9(391):ePub - PMID: 28539475 - PMCID: PMC5917603 - DOI: 10.1126/scitranslmed.aal4682
Bruns OT, Bischof TS, Harris DK, Franke D, Shi Y, Riedemann L, Bartelt A, Jaworski FB, Carr JA, Rowlands CJ, Wilson MWB, Chen O, Wei H, Hwang GW, Montana DM, Coropceanu I, Achorn OB, Kloepper J, Heeren J, So PTC, Fukumura D, Jensen KF, Jain RK, Bawendi MG
Next-generation in vivo optical imaging with short-wave infrared quantum dots.
Nat Biomed Eng. 2017;1:ePub - PMID: 29119058 - PMCID: PMC5673283 - DOI: 10.1038/s41551-017-0056
Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK
Corrigendum: Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity.
Cold Spring Harb Perspect Med. 2016;6(12):ePub - PMID: 27908927 - PMCID: PMC5131752 - DOI: 10.1101/cshperspect.a031195
Rahbari NN, Kedrin D, Incio J, Liu H, Ho WW, Nia HT, Edrich CM, Jung K, Daubriac J, Chen I, Heishi T, Martin JD, Huang Y, Maimon N, Reissfelder C, Weitz J, Boucher Y, Clark JW, Grodzinsky AJ, Duda DG, Jain RK, Fukumura D
Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases.
Sci Transl Med. 2016;8(360):360ra135 - PMID: 27733559 - PMCID: PMC5457741 - DOI: 10.1126/scitranslmed.aaf5219
Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK
Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity.
Cold Spring Harb Perspect Med. 2016;6(12):ePub - PMID: 27663981 - PMCID: PMC5131751 - DOI: 10.1101/cshperspect.a027094
Meijer EF, Baish JW, Padera TP, Fukumura D
Measuring Vascular Permeability In Vivo.
Methods Mol Biol. 2016;1458:71-85 - PMID: 27581015 - PMCID: PMC5435480 - DOI: 10.1007/978-1-4939-3801-8_6
Patil MD, Bhaumik J, Babykutty S, Banerjee UC, Fukumura D
Arginine dependence of tumor cells: targeting a chink in cancer's armor.
Oncogene. 2016;35(38):4957-72 - PMID: 27109103 - PMCID: PMC5457742 - DOI: 10.1038/onc.2016.37
Kloepper J, Riedemann L, Amoozgar Z, Seano G, Susek K, Yu V, Dalvie N, Amelung RL, Datta M, Song JW, Askoxylakis V, Taylor JW, Lu-Emerson C, Batista A, Kirkpatrick ND, Jung K, Snuderl M, Muzikansky A, Stubenrauch KG, Krieter O, Wakimoto H, Xu L, Munn LL, Duda DG, Fukumura D, Batchelor TT, Jain RK
Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival.
Proc Natl Acad Sci U S A. 2016;113(16):4476-81 - PMID: 27044098 - PMCID: PMC4843473 - DOI: 10.1073/pnas.1525360113
13