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Rakesh Jain
Director, A.W. Cook Professor of Tumor Biology

Jain Lab Research

Tumor Vessels and Microenvironment: Bench to Bedside and Back A solid tumor is an organ composed of cancer cells and host stromal cells, which are nourished by the vasculature and embedded in an extra-cellular matrix. The interaction among these cells, the surrounding matrix, and the local cellular microenvironment influences the expression of certain genes, whose products control the pathophysiological characteristics of the tumor, govern tumor progression, and affect the tumor's response to various therapies. Blood and lymphatic vessels also serve as conduits for metastatic spread. The over arching goal of our research is to dissect the pathophysiology of the vascular and extra-vascular components of tumors, to determine the role of tumor-host interactions in tumor biology, and ultimately to translate this knowledge into improved cancer detection, prevention, and treatment in humans. To unravel the complex biology of tumors, we have developed an array of imaging technologies, mathematical models, and sophisticated animal preparations. These include multiphoton microscopy and genetically engineered mice with surgically implanted transparent windows, which permit the in vivo visualization of gene expression and function in tumors and their surrounding host stroma. This undertaking has provided unprecedented molecular, cellular, anatomical, and functional insights into the vascular, interstitial and cellular barriers to cancer treatment. Our laboratory found that high interstitial pressure is a universal characteristic of solid tumors, and that it can impair the delivery of molecular medicine within tumors, induce peri-tumor edema and contribute to lymphatic metastasis. We have identified the mechanisms underlying this elevated pressure: high vascular permeability, lack of functional lymphatics, and mechanical stress generated by tumor growth. Overexpression of the lymphangiogenic factor VEGF-C increases lymph node metastasis, but does not increase lymphatic function or decrease the interstitial pressure. However, judicious application of antiangiogenic agents can lower the pressure and improve the delivery and efficacy of various cancer treatments. To gain a deeper insight of tumor microenvironment, we measured interstitial convection, diffusion, and binding using photobleaching, and pO2 and pH profiles around individual tumor vessels using phosphorescence quenching and ratio imaging. We proposed the novel hypothesis that the anomalous assembly of the collagen network can prevent the penetration of therapeutic agents in tumors, and showed that the hormone relaxin, bacterial collagenase, MMP1/8 and anti-hypertensive drugs can improve drug distribution by modifying this network. Our finding that angiogenic molecules regulate adhesion molecules on the vasculature provided the first link between the disparate fields of angiogenesis and adhesion, and revealed a novel mechanism by which tumors evade immune recognition. In collaboration with Dr. Brian Seed, we discovered that cancer cells co-opt the host stromal cells and entice them to produce pro- and anti-angiogenic growth factors. By revealing that host cells are not passive bystanders, but active participants in tumor angiogenesis, growth, metastasis, and therapeutic response, our laboratory provided a rational basis for combining Herceptin with VEGF blockade for the treatment of breast cancer – a concept that led to a clinical trial. Our work has revealed that the malfunction of the vascular and extravascular compartments in solid tumors often thwarts the effectiveness of both conventional and novel therapies. Our laboratory is most celebrated for a new hypothesis that antiangiogenic therapy can "normalize" the abnormal tumor vasculature and improve both the delivery and efficacy of therapeutics. We have validated this concept in rectal carcinoma and glioblastoma patients receiving antiangiogenic therapy and in the process, discovered potential biomarkers of tumor escape from these therapies. Now we are exploring novel strategies to expand the window of normalization and seeking potential biomarkers for tailoring therapies to individuals. By integrating principles from physiology, pharmacology, immunology, and molecular biology, our laboratory has developed mathematical models of drug delivery and pathophysiological processes in solid tumors. These modeling tools have allowed us to extract simple, important principles that should spark the development of novel diagnostic and therapeutic strategies. h2. Rakesh K. Jain receives National Medal of Science at the White House! ->Click here for the webcast.


 Click here for Dr. Jain's CV

Lab News

Glioma subtypes determine how the dangerous brain tumors spread, evade anti-angiogenic treatment

Molecular signatures of anti-angiogenic resistant cells could provide new treatment targets.

Read Press Release

Intersecting Paths, Unprecedented Journeys

They haven’t seen each other in about a year and a half, but once they’ve shaken hands, their conversation immediately turns to science. When your work has the potential to save millions of lives, that’s what you do.

Rakesh K. Jain, COE74M, 76PhD, has spent decades working on some of the world’s most pressing health problems, and has  come to be regarded as one of America’s most accomplished scientists. Arup K. Chakraborty, COE88PhD, is tackling one of the world’s most elusive challenges: creating a vaccine for the human immunodeficiency virus (HIV), the causative agent of AIDS.

Read the full story at University of Delaware ...

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


Healthcare Pioneer Rakesh Jain Honored at New England Choice Awards Gala –India New England News profile of MGH investigator
Lymph node metastases may not always be the source of cancer's spread to other organs

"What did the lymph nodes show?" is the question whose answer is apprehensively awaited by every colon cancer patient. Even in the age of molecular medicine, the absence or presence of colon cancer spread to regional lymph nodes remains the strongest predictor of whether surgery has cured the cancer, or whether an individucal may harbor occult metastatic disease and thus require adjuvant chemotherapy to reduce the risk of lethal cancer metastasese recurring in distant organs.

Press release ... 
Editorial in Science ...

Jain Lab Team

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

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

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

Polarization of tumor-associated macrophages: a novel strategy for vascular normalization and antitumor immunity.

TAMs with M2-like phenotype lead to abnormal tumor vasculature by producing angiogenic factors, such as PlGF, and M2-cytokines, such as IL10 and CCL22. In addition, M2-cytokines suppress immune cell functions. Elevated levels of HRG polarize TAMs away from an M2-like phenotype to normalize tumor vessels and activate anti-tumor immunity. By fortifying tumor vessels, vascular normalization may decrease shedding of metastatic cells into circulation resulting in decreased metastasis. Normalized vessels may also facilitate delivery of drugs and immune cells. Reduction in hypoxia – known to increase resistance to radiation and a number of therapeutics – also sensitizes tumors to various therapies and decreases selection pressure for more malignant clone, and promotes M1-like TAM phenotype. All these effects of HRG treatment may result in decreased tumor growth and metastasis and increased efficacy of various therapies. PlGF deletion in macrophages can phenocopy many effects of HRG treatment. (Schematics of abnormal and normalized tumor vasculature reproduced from Jain, Nat Med 7:987, 2001).

Cancer Cell. 2011;19(1):1-2 - PMID: 21251607 - PMCID: PMC3037265 - DOI: 10.1016/j.ccr.2011.01.005


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

Jain Lab Careers

Postdoctoral Fellow

Investigator: Jain, Rakesh
Date Posted: 2017-01-13
Description
The Steele Laboratory is currently seeking a postdoctoral applicant with expertise in breast cancer cell signaling and microenvironment. The position requires a highly motivated and independent researcher to carry out a project aimed at exploring brain-dependent signaling mechanisms to overcome resistance to targeted therapy andto restore anti-tumor immunity. Please see our recent papers for more information about our focus and experimental setup: 1) Askoxylakis et. al., Preclinical Efficacy of Ado-trastuzumab Emtansine in the Brain Microenvironment, JNCI 2015 2) Kodack et. al., Emerging strategies for treating brain metastases from breast cancer, Cancer Cell 2015. Experience in the following technical areas is preferred: molecular and cell biology, biochemistry, flow cytometry and FACS, immunohistochemistry and imaging, and murine models of cancer.
Requirements
Individuals must have a Ph.D. and/or M.D., appropriate research experience, strong organizational, interpersonal, communication, and computer skills and be prepared to work in a dynamic team environment. Applicants with a strong training background and publication track record in brain tumors are highly encouraged to apply. Experience in the following technical areas is preferred: immunohistochemistry, imaging and murine models of cancer. To begin the application process, please e-mail a current CV and statement of purpose to jobs@steele.mgh.harvard.edu

Postdoctoral Fellowship in Tuberculosis Granuloma Microenvironment

Investigator: Jain, Rakesh
Date Posted: 2017-01-13
Description
The Steele Laboratories are currently seeking postdoctoral applicants with expertise in tuberculosis research with extensive experience in immunohistochemistry and tuberculosis pathology. Experience with image analysis is highly preferred. The postdoctoral fellow will participate in an exciting multidisciplinary project aimed at studying the vasculature and matrix of tuberculosis granulomas. The project is funded by the Bill and Melinda Gates Foundation to Prof. Rakesh Jain, with leading tuberculosis collaborators from the NIH and Rutgers University.
Requirements
Individuals must have a Ph.D. and/or M.D., appropriate research experience, strong organizational, interpersonal, communication, and computer skills and be prepared to work in a dynamic team environment. US citizens and permanent US residents are encouraged to apply. To begin the application process, please e-mail a current CV and statement of purpose tojobs@steele.mgh.harvard.edu

Postdoctoral Fellowship in Glioblastoma Microenvironment and Anti-Tumor Immunity

Investigator: Jain, Rakesh
Date Posted: 2017-01-13
Description
The Steele Laboratories are currently seeking postdoctoral applicants with expertise in glioblastoma immunity and microenvironment to explore alternatives to current anti-VEGF treatment and modulation of the associated tumor immune component. Applicants with a strong training background and publication track record in immunology are highly encouraged to apply. Experience in the following technical areas is preferred: molecular and cell biology, flow cytometry and FACS, immunohistochemistry and imaging, and murine models of cancer.
Requirements
Individuals must have a Ph.D. and/or M.D., appropriate research experience, strong organizational, interpersonal, communication, and computer skills and be prepared to work in a dynamic team environment. US citizens and permanent US residents are encouraged to apply. To begin the application process, please e-mail a current CV and statement of purpose to jobs@steele.mgh.harvard.edu

Postdoctoral Fellow in Brain Tumors and Intravital Microscopy

Investigator: Jain, Rakesh
Date Posted: 2017-01-13
Description
The Steele Laboratory is currently seeking a postdoctoral applicant with training and research experience in tumor biology to carry out exciting multidisciplinary projects aimed at understanding tumor microenvironment in brain tumors. Expertise in animal studies and intravital imaging are necessary for the study.
Requirements
Individuals must have a Ph.D. and/or M.D., appropriate research experience, strong organizational, interpersonal, communication, and computer skills and be prepared to work in a dynamic team environment. Applicants with a strong training background and publication track record in brain tumors are highly encouraged to apply. Experience in the following technical areas is preferred: immunohistochemistry, imaging and murine models of cancer. To begin the application process, please e-mail a current CV and statement of purpose to jobs@steele.mgh.harvard.edu

Postdoctoral Fellow in pediatric brain tumors

Investigator: Jain, Rakesh
Date Posted: 2017-01-13
Description
The Steele Laboratory is currently seeking a postdoctoral applicant with training and research experience in tumor biology to carry out exciting multidisciplinary projects aimed at understanding the tumor micro-environment in pediatric brain tumors. Expertise in molecular biology, immunology, animal study and intra-vital imaging are necessary for the study.
Responsibilities
Individuals must have a Ph.D. and/or M.D., appropriate research experience, strong organizational, interpersonal, communication, and computer skills and be prepared to work in a dynamic team environment. Experience in the following technical areas is preferred: molecular and cell biology, flow cytometry and FACS, immunohistochemistry, imaging and murine models of cancer. To begin the application process, please e-mail a current CV and statement of purpose to jobs@steele.mgh.harvard.edu

Selected Publications (from total of 723)

Reardon DA, Lassman AB, Schiff D, Yunus SA, Gerstner ER, Cloughesy TF, Lee EQ, Gaffey SC, Barrs J, Bruno J, Muzikansky A, Duda DG, Jain RK, Wen PY
Phase 2 and biomarker study of trebananib, an angiopoietin-blocking peptibody, with and without bevacizumab for patients with recurrent glioblastoma.
Cancer. 2017;124(7):1438-1448 - PMID: 29266174 - DOI: 10.1002/cncr.31172
Mitchell MJ, Jain RK, Langer R
Engineering and physical sciences in oncology: challenges and opportunities.
Nat Rev Cancer. 2017;17(11):659-675 - PMID: 29026204 - PMCID: PMC5683724 - DOI: 10.1038/nrc.2017.83
Pinter M, Jain RK
Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy.
Sci Transl Med. 2017;9(410):ePub - PMID: 28978752 - PMCID: PMC5928511 - DOI: 10.1126/scitranslmed.aan5616
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
Nia HT, Liu H, Seano G, Datta M, Jones D, Rahbari N, Incio J, Chauhan VP, Jung K, Martin JD, Askoxylakis V, Padera TP, Fukumura D, Boucher Y, Hornicek FJ, Grodzinsky AJ, Baish JW, Munn LL, Jain RK
Solid stress and elastic energy as measures of tumour mechanopathology.
Nat Biomed Eng. 2016;1:ePub - PMID: 28966873 - PMCID: PMC5621647 - DOI: 10.1038/s41551-016-0004
Jain RK
Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia.
Cancer Cell. 2014;26(5):605-622 - PMID: 25517747 - PMCID: PMC4269830 - DOI: 10.1016/j.ccell.2014.10.006
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