DF/HCC Program Affiliation

Angiogenesis, Invasion and Metastasis

Lab Website

Steele Lab

Research Abstract

My work is devoted to research in adult stem cell biology and their role in tumor angiogenesis, growth and metastasis. The long-term goal of my research is to gain fundamental insight into solid tumor cellular biology and to directly translate this knowledge into improved therapies by conducting correlative studies in clinical trials in cancer patients.
Adult stem cells of bone marrow origin may directly or indirectly participate in the process of new vessel formation in tumors, and their involvement may be critical for tumor growth. However, controversial evidence has been offered for some of the same tumor models in regard to the role of bone marrow-derived cells (BMDCs, Cancer Cell 2003). I overcame these problems by using genetic tagging with green fluorescent protein, mouse transparent window models, and intravital multiphoton laser scanning microscopy (MPLSM), and demonstrated that the contribution of BMDCs to functional tumor endothelium is marginal, and dependent on tumor type, stage, site, and mouse strain (Blood 2006). The major contribution of BMDCs was carried out by myelo-monocytes, which are recruited to tumors in part due to VEGFR1 activation in BMDCs (PLoS One 2009). Nevertheless, we have also shown that metastases form independently from VEGFR1 signaling (Nature 2009). This work has been supported by the Cancer Research Institute, American Association for Cancer Research, Massachusetts General Hospital ECOR and National Cancer Institute (NCI).
In an ongoing clinical trial of bevacizumab in rectal cancer patients, I characterized multiple subpopulations of blood cells expressing endothelial markers (J Clin Oncol 2006 & 2007, Nat Protoc 2007). We found that enumerating these cells may be a useful biomarker for anti-angiogenic therapy (Nat Med 2004, J Clin Oncol 2005 & 2009). Moreover, I recently showed that quantification of these cells in the peripheral blood of recurrent glioblastoma and hepatocellular carcinoma patients is a potentially reliable surrogate marker of response (Cancer Cell 2007, J Clin Oncol 2009). I am currently evaluating these cells in pediatric tumors, and sarcoma, ovarian and head-and-neck cancer patients in NCI-funded trials (Nat Rev Clin Oncol 2009).
In addition, I established an in vivo system to investigate the functional vessel formation during adipogenic transformation of fat cell precursors, and uncovered the reciprocal regulation between adipogenesis and angiogenesis (Circ Res 2003) and the role of BMDCs (PLoS One 2009). Next, I demonstrated the transplantability of fat tissues and the role of VEGF using in vivo microscopy and various GFP-transgenic mice (Cancer Res 2004). Finally, we investigated comparatively adult and cord blood precursor cells as vascular cell sources for tissue engineering (Nat Biotechnol 2005, Blood 2007).
A significant portion of my time is dedicated to teaching experimental techniques through daily supervision of research fellows and graduate and undergraduate students. My trainees have already published and received awards from the Japanese Government, AHA, and Whitaker, Ford and Susan Komen Foundations. In the past three years, I have been teaching in the MIT-HMS Health, Science and Technology Program, in ASTRO and RTOG Translational Meetings for residents in Radiation Oncology, and in the yearly Methods in Bioengineering course that I am organizing in the Steele Laboratory at MGH.

Publications

• Dawson MR, Duda DG, Chae SS, Fukumura D, Jain RK.VEGFR1 activity modulates myeloid cell infiltration in growing lung metastases but is not required for spontaneous metastasis formation.PLoS ONE 2009;4(9):e6525.
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• Dawson MR, Duda DG, Fukumura D, Jain RK.VEGFR1-activity-independent metastasis formation.Nature 2009 Sep 17;461(7262):E4; discussion E5.
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• Sorensen AG,Batchelor TT,Zhang WT,Chen PJ,Yeo P,Wang M,Jennings D,Wen PY,Lahdenranta J,Ancukiewicz M,di Tomaso E,Duda DG,Jain RK.A "Vascular Normalization Index" as Potential Mechanistic Biomarker to Predict Survival after a Single Dose of Cedir
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• Jain RK,Duda DG,Willett CG,Sahani DV,Zhu AX,Loeffler JS,Batchelor TT,Sorensen AG.Biomarkers of response and resistance to antiangiogenic therapy.Nat Rev Clin Oncol 2009 Jun;6(6):327-338.
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• Willett CG,Duda DG,di Tomaso E,Boucher Y,Ancukiewicz M,Sahani DV,Lahdenranta J,Chung DC,Fischman AJ,Lauwers GY,Shellito P,Czito BG,Wong TZ,Paulson E,Poleski M,Vujaskovic Z,Bentley R,Chen HX,Clark JW,Jain RK.Efficacy, Safety, and Biomarkers of Neoadjuvant
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• Zhu AX,Sahani DV,Duda DG,di Tomaso E,Ancukiewicz M,Catalano OA,Sindhwani V,Blaszkowsky LS,Yoon SS,Lahdenranta J,Bhargava P,Meyerhardt J,Clark JW,Kwak EL,Hezel AF,Miksad R,Abrams TA,Enzinger PC,Fuchs CS,Ryan DP,Jain RK.Efficacy, Safety, and Potential Bioma
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• Jones R,Capen DE,Jacobson M,Cohen KS,Scadden DT,Duda DG.VEGFR2PDGFRbeta circulating precursor cells participate in capillary restoration after hyperoxia acute lung injury (HALI).J Cell Mol Med 2009 May 6.
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• Kamoun WS,Ley CD,Farrar CT,Duyverman AM,Lahdenranta J,Lacorre DA,Batchelor TT,di Tomaso E,Duda DG,Munn LL,Fukumura D,Sorensen AG,Jain RK.Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival
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• Duda DG,Jain RK,Willett CG.Antiangiogenics: the potential role of integrating this novel treatment modality with chemoradiation for solid cancers.J Clin Oncol 2007 Sep 10;25(26):4033-42.
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• Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT.Angiogenesis in brain tumours.Nat Rev Neurosci 2007 Aug;8(8):610-22.
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• Duda DG, Batchelor TT, Willett CG, Jain RK.VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects.Trends Mol Med 2007 Apr 24.
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• Duda DG, Cohen KS, Scadden DT, Jain RK.A protocol for phenotypic detection and enumeration of circulating endothelial cells and circulating progenitor cells in human blood.Nat Protoc 2007;2(4):805-10.
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• Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK.AZD2171, a pan-VEGF receptor ty
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• Jain RK, Duda DG, Clark JW, Loeffler JS.Lessons from phase III clinical trials on anti-VEGF therapy for cancer.Nat Clin Pract Oncol 2006 Jan;3(1):24-40.
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• Duda DG, Cohen KS, Kozin SV, Perentes JY, Fukumura D, Scadden DT, Jain RK.Evidence for incorporation of bone marrow-derived endothelial cells into perfused blood vessels in tumors.Blood 2006 Apr 1;107(7):2774-6.
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• Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK.Direct evi
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