Burnham Institute for Medical Research – Faculty

ERKKI RUOSLAHTI, M.D., PH.D.
Distinguished Professor
Tumor Microenvironment

805.893.5358 (phone)
805.893.5805 (fax)
ruoslahti@burnham.org

RESEARCH FOCUS, BIOGRAPHY, STAFF, PUBLICATIONS

Research Focus

The underlying themes of Dr. Ruoslahti’s work are tumor vasculature and metastasis. Tumors, like other tissues, contain both blood vessels and lymphatic vessels. A tumor needs blood vessels to be able to grow, and destroying tumor blood vessels is the basis of a promising new cancer therapy. Lymphatic vessels are not needed for tumor growth, but like blood vessels, the lymphatics are an important conduit of distant metastasis.

Vascular zip codes

The Ruoslahti laboratory screens large collections ("libraries") of random peptides to identify those that bind to specific targets in the vasculature. The peptides in the library are displayed on the surface of phage (a virus that infects bacteria), and the screening is done in vivo. When the library is injected into the circulation of a mouse, phage particles that display peptides capable of binding to a selected target tissue, such as a tumor, accumulate at the target where they can be collected and their peptide identified. The method has revealed a wealth of specific features, or "vascular zip codes", in the vessels of individual tissue and tumors. We have identified peptides that specifically home to tumors because they recognize angiogenesis-associated or tumor-type specific markers in tumor blood vessels. We even have peptides that distinguish the vessels of pre-malignant lesions from those of fully malignant tumors. Homing peptides have also revealed a zip code system of molecular changes in tumor lymphatics.

We have used synthetic homing peptides identified by phage display to target drugs and biologicals into tumors. The targeting can increase the efficacy of a drug while reducing its side effects. Even a non-specifically toxic compound can be converted into a compound that affects only the targeted tissue. We also identify the target molecules (receptors) for the peptides. The receptors of our tumor-homing peptides often play a functionally important role in tumor vasculature, and because of this are candidates for drug development.

Nanomedicine

A major recent focus is to use homing peptides as targeting elements to deliver nanoparticles into tumors and other sites of disease. Nanoparticles are considered a promising new approach in medicine because they can be designed to perform more functions than a simple drug. The vasculature is an excellent target for nanoparticles because tumor vessels are readily available for circulating particles. In collaboration with several chemistry and bioengineering laboratories, we have constructed multifunctional nanoparticles for tumor targeting. These particles can be directed into tumors in a highly selective manner as demonstrated by histology, non-invasive imaging, and tumor treatment results. We have constructed nanoparticles with the ability to amplify their own homing to tumors, and are currently working on nanoparticles coated peptides that confer the particles tissue-penetrating properties. The goal is to incorporate multiple functions such as specific targeting, self-amplification of the targeting, exit from vessels into tissue, ability to send signals for imaging, and controlled drug delivery. It is also important that the particles resist uptake by the reticuloendothelial system, which otherwise keeps them from reaching their intended target.

Cell attachment and anoikis

Cancer is so lethal because, unlike normal cells, cancer cells can migrate to distant sites where they do not belong and multiply there. The metastatic growths that result are what often makes cancer incurable. Normal cells attach to an insoluble protein scaffold, extracellular matrix, the protein/carbohydrate meshwork that fills the spaces in between cells. If normal cells detach from the extracellular matrix, they promptly die by apoptosis which, when caused by lack of attachment, is called anoikis. One of the fundamental characteristics of cancer cells is that they can detach and stay alive to eventually metastasize.

In the 1980's this laboratory demonstrated that the cell-binding site of fibronectin and several other extracellular matrix proteins consists of a tripeptide, RGD, presented in a different context in each protein. We also isolated RGD-binding cell-surface receptors that subsequently became known as the integrin family of cell-adhesion receptors. The RGD paradigm became the basis of an intense worldwide drug development program seeking new treatments for arterial restenosis, thrombosis, angiogenesis, and cancer.

The current cell attachment work in this laboratory focuses on the signaling pathways that control anoikis, and through it metastasis and even angiogenesis. The signaling proteins we work on include Bit1 a mitochondrial protein we consider a "guardian of anoikis", a protein we named "metadherin" because it promotes lung metastasis from breast cancers, and the receptor for one of our tumor-homing peptides that appears to promote tumor growth by causing metabolic changes in tumor cells.

Designing Multifunctional Nanoparticles for Tumor Delivery

Biography

Erkki Ruoslahti earned his M.D. and Ph.D. from the University of Helsinki in Finland in 1967. After postdoctoral training at the California Institute of Technology, he held various academic appointments with the University of Helsinki and the University of Turku in Finland and City of Hope National Medical Center in Duarte, California. He joined The Burnham Institute in 1979 and served as its President from 1989-2002. He has been a Distinguished Professor at UCSB in Biological Sciences since 2005. His honors include: elected membership to the U.S. National Academy of Sciences, Institute of Medicine, American Academy of Arts and Sciences, and the European Molecular Biology Organization. He is the recipient of the G.H.A. Clowes Award, Robert J. and Claire Pasarow Foundation Award, Jacobaeus International Prize, The Jubilee Award given by the British Biomedical Society. He was a Nobel Fellow at the Karolinska Institute in Stockholm in 1995, and is an Honorary Doctor of Medicine from the University of Lund, as well as a Knight of the Order of the White Rose of Finland. Dr. Ruoslahti is the recipient of the 2005 Japan Prize in Cell Biology.

Staff

The Ruoslahti laboratory in Santa Barbara is a branch of Burnham Institute for Medical Research affiliated with UCSB. It consists of five postdoctoral fellows, two staff scientists, two graduate students, one lab assistant, and a laboratory manager. Two postdoctoral fellows, one research assistant, one graduate student, one visiting researcher, and a lab assistant work in the La Jolla laboratory on the Burnham main campus.

Ruoslahti laboratory in Santa Barbara

Lilach Agemy, Ph.D.
Chris Brunquell
Renwei Chen, M.D., Ph.D.
Sazid Hussain, Ph.D.
Poornima Kolhar
V. Ramana Kotamraju, Ph.D.
Joshua Olson
Lise Roth, Ph.D.
Barry Rowan
Kazuki Sugahara, MD, PhD
Tambet Teesalu, PhD

Ruoslahti laboratory in La Jolla

Ying Chao
Valentina Fogal, PhD
Priya Karmali, Ph.D.
Matt Kinsella
Michael Oolie
Ji-Ho Park

Selected Publications

Lee S-M., Hong H-Y., Kwon T-H., Choi J-Y., Park R-W., Kim I-S., Kwon T-G., Yoo E-S., Yoon G-S., Ruoslahti E., and Lee, B-H. Targeting bladder tumor cells in vivo in the urine with a peptide identified by phage display. Molec. Canc. Res. 5:11-19 (2007).

Simberg, D., Duza T., Park, J.H., Essler M., Pilch, J., Zhang, L., Derfus A.M., Yang M., Hoffman R.M. Bhatia S., Sailor, M.J., and Ruoslahti, E. Biomimetic amplification of nanoparticle homing to tumors. Proc. Natl. Acad. Sci. USA 104:932-936 (2007).

Sugahara K., Sugiyama D., Byrne J., Don P., Wolf D.P., Lowitz K.P., Kobayashi Y., Kabir-Salmani M., Nadano D., Aoki D., Nozawa S., Nakayama J., Mustelin T., Ruoslahti E., Yamaguchi N., and Fukuda, M.N. Trophoblast cell activation by trophinin ligation: Possible role in human embryo implantation. Proc. Natl. Acad. Sci. USA 104:3799-3804 (2007).

Jarvinen T. and Ruoslahti E. Molecular changes in the vasculature of injured tissues Am. J. Path. 171:702-711 (2007).

Derfus, A., Chen A., Dal-Hee M., Ruoslahti, E., Bhatia, S. Targeted Quantum Dot Conjugates for siRNA Delivery Bioconjugate Chem. 18:1391-1396 (2007).

Derfus, A., von Maltzahn G., Harris T., Duza T., Vecchio K., Ruoslahti, E., Bhatia S. Remotely triggered release from Magnetic Nanoparticles. Adv. Mat., 19:3932-3936 (2007).

Kairouz-Wahbe, R., Biliran H., Xiuquan L., IngWei K., Wankell M., Besch-Williford C., Pascual J., Oshima R., and Ruoslahti E. Anoikis effector Bit1 Negatively regulates Erk activity. Proc. Natl. Acad. Sci. USA 105:1528-1532 (2008).

Park, J-H., von Maltzahn, G., Zhang, L., Schwartz, M. P., Bhatia, S. N., Ruoslahti, E., Sailor, M. J. Magnetic Iron Oxide Nanoworms for Tumor Targeting and Imaging. Adv. Mater. 20(9):1630-1635 (2008).

von Maltzahn, G., Ren, Y., Park, J-H., Min, D-H., Kotamraju, V.R., Jayakumar, J., Fogal, V., Sailor, M., Ruoslahti, E., and Bhatia, S.N. In vivo Tumor Cell Targeting with “Click” Nanoparticles. Bioconjug. Chem. 19:1570-1578 (2008).

Laakkonen, P., Zhang, L., Ruoslahti, E. Peptide targeting of tumor lymph vessels. Ann. N.Y. Acad. Sci., 1131:37-43 (2008).

Zhang, H., Kusunose, J., Kheirolomoom, A., Seo, J.W., Qi, J.Y., Watson, K.D., Lindfors, H.A., Ruoslahti, E., Sutcliffe, J.L., Ferrara, K.W. Dynamic imaging of arginine-rich heart-targeted vehicles in a mouse model. Biomaterials, 29:1976-1988 (2008).

Fogal, V., Zhang, L., and Ruoslahti, E. Mitochondrial/Cell surface protein p32/gC1qR as a molecular target in tumor cells and tumor stroma. Cancer Res. 68:7210-7218 (2008).

Karmali, P.P., Kotamraju, V.R., Kastantin, M., Black, M., Missirlis, D, Tirrell, M., and Ruoslahti, E. Targeting of albumin-embedded taxol nanoparticles to tumors. Nanomedicine. 5(1):73-82 (2008).

Park, J-H., von Maltzahn, G., Ruoslahti, E., Bhatia, S.N., Sailor, M.J. Micellar Hybrid Nanoparticles for Simultaneous Magnetofluorescent Imaging and Drug Delivery. Angew. Chem. Int. Ed. 47(38):7284-7288 (2008).

Biliran, H., Jan, Y., Chen, R., Elena B., Pasquale, E., and Ruoslahti, E. Protein kinase D is a positive regulator of Bit1 apoptotic function. J. Biol. Chem. 283(42): 28029-28037 (2008).

List of Publications via PubMed
(NIH National Library of Medicine)

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	Print Version ERKKI RUOSLAHTI, M.D., PH.D. Distinguished Professor Tumor Microenvironment 805.893.5358 (phone) 805.893.5805 (fax) ruoslahti@burnham.org RESEARCH FOCUS, BIOGRAPHY, STAFF, PUBLICATIONS Research Focus The underlying themes of Dr. Ruoslahti’s work are tumor vasculature and metastasis. Tumors, like other tissues, contain both blood vessels and lymphatic vessels. A tumor needs blood vessels to be able to grow, and destroying tumor blood vessels is the basis of a promising new cancer therapy. Lymphatic vessels are not needed for tumor growth, but like blood vessels, the lymphatics are an important conduit of distant metastasis. Vascular zip codes The Ruoslahti laboratory screens large collections ("libraries") of random peptides to identify those that bind to specific targets in the vasculature. The peptides in the library are displayed on the surface of phage (a virus that infects bacteria), and the screening is done in vivo. When the library is injected into the circulation of a mouse, phage particles that display peptides capable of binding to a selected target tissue, such as a tumor, accumulate at the target where they can be collected and their peptide identified. The method has revealed a wealth of specific features, or "vascular zip codes", in the vessels of individual tissue and tumors. We have identified peptides that specifically home to tumors because they recognize angiogenesis-associated or tumor-type specific markers in tumor blood vessels. We even have peptides that distinguish the vessels of pre-malignant lesions from those of fully malignant tumors. Homing peptides have also revealed a zip code system of molecular changes in tumor lymphatics. We have used synthetic homing peptides identified by phage display to target drugs and biologicals into tumors. The targeting can increase the efficacy of a drug while reducing its side effects. Even a non-specifically toxic compound can be converted into a compound that affects only the targeted tissue. We also identify the target molecules (receptors) for the peptides. The receptors of our tumor-homing peptides often play a functionally important role in tumor vasculature, and because of this are candidates for drug development. Nanomedicine A major recent focus is to use homing peptides as targeting elements to deliver nanoparticles into tumors and other sites of disease. Nanoparticles are considered a promising new approach in medicine because they can be designed to perform more functions than a simple drug. The vasculature is an excellent target for nanoparticles because tumor vessels are readily available for circulating particles. In collaboration with several chemistry and bioengineering laboratories, we have constructed multifunctional nanoparticles for tumor targeting. These particles can be directed into tumors in a highly selective manner as demonstrated by histology, non-invasive imaging, and tumor treatment results. We have constructed nanoparticles with the ability to amplify their own homing to tumors, and are currently working on nanoparticles coated peptides that confer the particles tissue-penetrating properties. The goal is to incorporate multiple functions such as specific targeting, self-amplification of the targeting, exit from vessels into tissue, ability to send signals for imaging, and controlled drug delivery. It is also important that the particles resist uptake by the reticuloendothelial system, which otherwise keeps them from reaching their intended target. Cell attachment and anoikis Cancer is so lethal because, unlike normal cells, cancer cells can migrate to distant sites where they do not belong and multiply there. The metastatic growths that result are what often makes cancer incurable. Normal cells attach to an insoluble protein scaffold, extracellular matrix, the protein/carbohydrate meshwork that fills the spaces in between cells. If normal cells detach from the extracellular matrix, they promptly die by apoptosis which, when caused by lack of attachment, is called anoikis. One of the fundamental characteristics of cancer cells is that they can detach and stay alive to eventually metastasize. In the 1980's this laboratory demonstrated that the cell-binding site of fibronectin and several other extracellular matrix proteins consists of a tripeptide, RGD, presented in a different context in each protein. We also isolated RGD-binding cell-surface receptors that subsequently became known as the integrin family of cell-adhesion receptors. The RGD paradigm became the basis of an intense worldwide drug development program seeking new treatments for arterial restenosis, thrombosis, angiogenesis, and cancer. The current cell attachment work in this laboratory focuses on the signaling pathways that control anoikis, and through it metastasis and even angiogenesis. The signaling proteins we work on include Bit1 a mitochondrial protein we consider a "guardian of anoikis", a protein we named "metadherin" because it promotes lung metastasis from breast cancers, and the receptor for one of our tumor-homing peptides that appears to promote tumor growth by causing metabolic changes in tumor cells. Designing Multifunctional Nanoparticles for Tumor Delivery Biography Erkki Ruoslahti earned his M.D. and Ph.D. from the University of Helsinki in Finland in 1967. After postdoctoral training at the California Institute of Technology, he held various academic appointments with the University of Helsinki and the University of Turku in Finland and City of Hope National Medical Center in Duarte, California. He joined The Burnham Institute in 1979 and served as its President from 1989-2002. He has been a Distinguished Professor at UCSB in Biological Sciences since 2005. His honors include: elected membership to the U.S. National Academy of Sciences, Institute of Medicine, American Academy of Arts and Sciences, and the European Molecular Biology Organization. He is the recipient of the G.H.A. Clowes Award, Robert J. and Claire Pasarow Foundation Award, Jacobaeus International Prize, The Jubilee Award given by the British Biomedical Society. He was a Nobel Fellow at the Karolinska Institute in Stockholm in 1995, and is an Honorary Doctor of Medicine from the University of Lund, as well as a Knight of the Order of the White Rose of Finland. Dr. Ruoslahti is the recipient of the 2005 Japan Prize in Cell Biology. Staff The Ruoslahti laboratory in Santa Barbara is a branch of Burnham Institute for Medical Research affiliated with UCSB. It consists of five postdoctoral fellows, two staff scientists, two graduate students, one lab assistant, and a laboratory manager. Two postdoctoral fellows, one research assistant, one graduate student, one visiting researcher, and a lab assistant work in the La Jolla laboratory on the Burnham main campus. Ruoslahti laboratory in Santa Barbara Lilach Agemy, Ph.D. Chris Brunquell Renwei Chen, M.D., Ph.D. Sazid Hussain, Ph.D. Poornima Kolhar V. Ramana Kotamraju, Ph.D. Joshua Olson Lise Roth, Ph.D. Barry Rowan Kazuki Sugahara, MD, PhD Tambet Teesalu, PhD Ruoslahti laboratory in La Jolla Ying Chao Valentina Fogal, PhD Priya Karmali, Ph.D. Matt Kinsella Michael Oolie Ji-Ho Park Selected Publications Lee S-M., Hong H-Y., Kwon T-H., Choi J-Y., Park R-W., Kim I-S., Kwon T-G., Yoo E-S., Yoon G-S., Ruoslahti E., and Lee, B-H. Targeting bladder tumor cells in vivo in the urine with a peptide identified by phage display. Molec. Canc. Res. 5:11-19 (2007). Simberg, D., Duza T., Park, J.H., Essler M., Pilch, J., Zhang, L., Derfus A.M., Yang M., Hoffman R.M. Bhatia S., Sailor, M.J., and Ruoslahti, E. Biomimetic amplification of nanoparticle homing to tumors. Proc. Natl. Acad. Sci. USA 104:932-936 (2007). Sugahara K., Sugiyama D., Byrne J., Don P., Wolf D.P., Lowitz K.P., Kobayashi Y., Kabir-Salmani M., Nadano D., Aoki D., Nozawa S., Nakayama J., Mustelin T., Ruoslahti E., Yamaguchi N., and Fukuda, M.N. Trophoblast cell activation by trophinin ligation: Possible role in human embryo implantation. Proc. Natl. Acad. Sci. USA 104:3799-3804 (2007). Jarvinen T. and Ruoslahti E. Molecular changes in the vasculature of injured tissues Am. J. Path. 171:702-711 (2007). Derfus, A., Chen A., Dal-Hee M., Ruoslahti, E., Bhatia, S. Targeted Quantum Dot Conjugates for siRNA Delivery Bioconjugate Chem. 18:1391-1396 (2007). Derfus, A., von Maltzahn G., Harris T., Duza T., Vecchio K., Ruoslahti, E., Bhatia S. Remotely triggered release from Magnetic Nanoparticles. Adv. Mat., 19:3932-3936 (2007). Kairouz-Wahbe, R., Biliran H., Xiuquan L., IngWei K., Wankell M., Besch-Williford C., Pascual J., Oshima R., and Ruoslahti E. Anoikis effector Bit1 Negatively regulates Erk activity. Proc. Natl. Acad. Sci. USA 105:1528-1532 (2008). Park, J-H., von Maltzahn, G., Zhang, L., Schwartz, M. P., Bhatia, S. N., Ruoslahti, E., Sailor, M. J. Magnetic Iron Oxide Nanoworms for Tumor Targeting and Imaging. Adv. Mater. 20(9):1630-1635 (2008). von Maltzahn, G., Ren, Y., Park, J-H., Min, D-H., Kotamraju, V.R., Jayakumar, J., Fogal, V., Sailor, M., Ruoslahti, E., and Bhatia, S.N. In vivo Tumor Cell Targeting with “Click” Nanoparticles. Bioconjug. Chem. 19:1570-1578 (2008). Laakkonen, P., Zhang, L., Ruoslahti, E. Peptide targeting of tumor lymph vessels. Ann. N.Y. Acad. Sci., 1131:37-43 (2008). Zhang, H., Kusunose, J., Kheirolomoom, A., Seo, J.W., Qi, J.Y., Watson, K.D., Lindfors, H.A., Ruoslahti, E., Sutcliffe, J.L., Ferrara, K.W. Dynamic imaging of arginine-rich heart-targeted vehicles in a mouse model. Biomaterials, 29:1976-1988 (2008). Fogal, V., Zhang, L., and Ruoslahti, E. Mitochondrial/Cell surface protein p32/gC1qR as a molecular target in tumor cells and tumor stroma. Cancer Res. 68:7210-7218 (2008). Karmali, P.P., Kotamraju, V.R., Kastantin, M., Black, M., Missirlis, D, Tirrell, M., and Ruoslahti, E. Targeting of albumin-embedded taxol nanoparticles to tumors. Nanomedicine. 5(1):73-82 (2008). Park, J-H., von Maltzahn, G., Ruoslahti, E., Bhatia, S.N., Sailor, M.J. Micellar Hybrid Nanoparticles for Simultaneous Magnetofluorescent Imaging and Drug Delivery. Angew. Chem. Int. Ed. 47(38):7284-7288 (2008). Biliran, H., Jan, Y., Chen, R., Elena B., Pasquale, E., and Ruoslahti, E. Protein kinase D is a positive regulator of Bit1 apoptotic function. J. Biol. Chem. 283(42): 28029-28037 (2008). List of Publications via PubMed (NIH National Library of Medicine)
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