Yves Boucher
Associate Prof., Radiation Oncology

Boucher Lab Research

Delivery of Oncolytic Viruses and Large Therapeutic Agents in Tumors

The therapeutic success of oncolytic viruses and other nanotherapeutics is severely limited by their poor diffusion and distribution through the tumor interstitial space. We have shown that collagen fibers in the tumor interstitial matrix hinder the diffusion of large molecules, and the penetration of viral particles. We used relaxin – a small hormone which stimulates the secretion of matrix metalloproteinases and inhibits collagen synthesis – to improve the diffusion of large molecules in collagen-rich tumors. Multiphoton laser scanning microscopy (MPLSM) and second harmonic generation (SHG) imaging of collagen fibers in living tumors demonstrated that relaxin enhances collagen degradation. We also found that bacterial collagenase or mammalian collagenases – matrix metallo-proteinase-1 or -8 – can improve the intratumoral penetration and anti-tumor efficacy of oncolytic viruses. We recently tested if losartan – a clinically approved angiotensin II receptor blocker (ARB) with noted anti-fibrotic activity – can enhance the penetration and efficacy of nanomedicine. We found that losartan led to a dose-dependent reduction in stromal collagen in several tumor models in mice. Furthermore, losartan improved vascular perfusion, the distribution and therapeutic effectiveness of oncolytic viruses, Doxil and small cytotoxic agents. Based on our experimental results with losartan, we initiated a clinical trial at Massachusetts General Hospital that will determine in patients with pancreatic cancer if losartan improves the effectiveness of small cytotoxic agents.

The narrow spacing between cancer cells is also a major barrier hindering the movement of oncolytic viruses and other nanotherapeutics. To bypass the cellular barrier, we tested the hypothesis that void spaces produced by cancer cell apoptosis improve the initial spread of oncolytic virus. In mice with mammary tumors, cancer cell apoptosis – induced by doxycycline-regulated expression/activation of caspase-8 or cytotoxic agents – enhanced the viral spread and therapeutic effectiveness of oncolytic virus injected intratumorally. In order to improve the systemic efficacy of nanotherapeutics targeted both at primary and metastatic tumors, it is also essential to identify agents that will improve the vascular extravasation of large therapeutics injected intravenously. We are testing if targeting tumor blood vessels, cancer cells, or both improves the delivery and effectiveness of nanotherapeutics.

Tumor Cell Migration and Metastasis

We are studying how the genetic modulation of matrix metalloproteinases or transcription factors affects cancer cell migration, fibrillar collagen and vascular basement membrane remodeling, lymph and blood vessel invasion, and lymph node and distant metastasis. We use MPLSM and tumors in transparent mammary windows to assess tumor cell migration phenotypes (e.g. amoeboid, mesenchymal) and velocity, and SHG imaging to visualize the interaction of cancer or stromal cells with collagen fibers.

Current Research

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

Mechanical compression drives cancer cells toward invasive phenotype

  Uncontrolled growth in a confined space generates mechanical compressive stress within tumors, but little is known about how such stress affects tumor cell behavior. Here we show that compressive stress stimulates migration of mammary carcinoma cells. The enhanced migration is accomplished by a subset of "leader cells" that extend filopodia at the leading edge of the cell sheet. Formation of these leader cells is dependent on cell microorganization and is enhanced by compressive stress. Accompanied by fibronectin deposition and stronger cell-matrix adhesion, the transition to leader-cell phenotype results in stabilization of persistent actomyosin-independent cell extensions and coordinated migration. Our results suggest that compressive stress accumulated during tumor growth can enable coordinated migration of cancer cells by stimulating formation of leader cells and enhancing cell-substrate adhesion. This novel mechanism represents a potential target for the prevention of cancer cell migration and invasion.

Proc Natl Acad Sci U S A. 2011;109(3):911-6 - PMID: 22203958 - PMCID: PMC3271885 - DOI: 10.1073/pnas.1118910109

Selected Publications (from total of 87)

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
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
Kumar V, Boucher Y, Liu H, Ferreira D, Hooker J, Catana C, Hoover AJ, Ritter T, Jain RK, Guimaraes AR
Noninvasive Assessment of Losartan-Induced Increase in Functional Microvasculature and Drug Delivery in Pancreatic Ductal Adenocarcinoma.
Transl Oncol. 2016;9(5):431-437 - PMID: 27751347 - PMCID: PMC5067928 - DOI: 10.1016/j.tranon.2016.07.004
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
Tolaney SM, Boucher Y, Duda DG, Martin JD, Seano G, Ancukiewicz M, Barry WT, Goel S, Lahdenrata J, Isakoff SJ, Yeh ED, Jain SR, Golshan M, Brock J, Snuderl M, Winer EP, Krop IE, Jain RK
Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients.
Proc Natl Acad Sci U S A. 2015;112(46):14325-14330 - PMID: 26578779 - PMCID: PMC4655544 - DOI: 10.1073/pnas.1518808112
Ager EI, Kozin SV, Kirkpatrick ND, Seano G, Kodack DP, Askoxylakis V, Huang Y, Goel S, Snuderl M, Muzikansky A, Finkelstein DM, Dransfield DT, Devy L, Boucher Y, Fukumura D, Jain RK
Blockade of MMP14 Activity in Murine Breast Carcinomas: Implications for Macrophages, Vessels, and Radiotherapy.
J Natl Cancer Inst. 2015;107(4):ePub - PMID: 25710962 - PMCID: PMC4402365 - DOI: 10.1093/jnci/djv017
Lee JJ, Perera RM, Wang H, Wu DC, Liu XS, Han S, Fitamant J, Jones PD, Ghanta KS, Kawano S, Nagle JM, Deshpande V, Boucher Y, Kato T, Chen JK, Willmann JK, Bardeesy N, Beachy PA
Stromal response to Hedgehog signaling restrains pancreatic cancer progression.
Proc Natl Acad Sci U S A. 2014;111(30):E3091-100 - PMID: 25024225 - PMCID: PMC4121834 - DOI: 10.1073/pnas.1411679111
Chauhan VP, Boucher Y, Ferrone CR, Roberge S, Martin JD, Stylianopoulos T, Bardeesy N, DePinho RA, Padera TP, Munn LL, Jain RK
Compression of Pancreatic Tumor Blood Vessels by Hyaluronan Is Caused by Solid Stress and Not Interstitial Fluid Pressure.
Cancer Cell. 2014;26(1):14-15 - PMID: 25026209 - PMCID: PMC4381566 - DOI: 10.1016/j.ccr.2014.06.003
Hong TS, Ryan DP, Borger DR, Blaszkowsky LS, Yeap BY, Ancukiewicz M, Deshpande V, Shinagare S, Wo JY, Boucher Y, Wadlow RC, Kwak EL, Allen JN, Clark JW, Zhu AX, Ferrone CR, Mamon HJ, Adams J, Winrich B, Grillo T, Jain RK, DeLaney TF, Fernandez-Del Castillo C, Duda DG
A Phase 1/2 and Biomarker Study of Preoperative Short Course Chemoradiation With Proton Beam Therapy and Capecitabine Followed By Early Surgery for Resectable Pancreatic Ductal Adenocarcinoma.
Int J Radiat Oncol Biol Phys. 2014;89(4):830-8 - PMID: 24867540 - PMCID: PMC4791180 - DOI: 10.1016/j.ijrobp.2014.03.034
Schwabl P, Payer BA, Grahovac J, Klein S, Horvatits T, Mitterhauser M, Stift J, Boucher Y, Trebicka J, Trauner M, Angermayr B, Fuhrmann V, Reiberger T, Peck-Radosavljevic M
Pioglitazone decreases portosystemic shunting by modulating inflammation and angiogenesis in cirrhotic and non-cirrhotic portal hypertensive rats.
J Hepatol. 2014;60(6):1135-42 - PMID: 24530596 - DOI: 10.1016/j.jhep.2014.01.025
Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, Popovic Z, Huang P, Bawendi MG, Boucher Y, Jain RK
Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels.
Nat Commun. 2013;4:2516 - PMID: 24084631 - PMCID: PMC3806395 - DOI: 10.1038/ncomms3516