Podcast: Artificial blood vessel visualizes cancer cell journey

Researchers from Johns Hopkins Institute for NanoBioTechnology are visualizing many of the steps involved in how cancer cells break free from tumors and travel through the blood stream, potentially on their way to distant organs.  Using an artificial blood vessel developed in the laboratory of Peter Searson, INBT director and professor of materials science and engineering, scientists are looking more closely into the complex journey of the cancer cell.

Figure 1. 3D projection of a confocal z-stack shows human umbilical vein endothelial cells (HUVECs) forming a functional vessel immunofluorescently stained for PECAM-1 (green) and nuclei (blue).

Figure 1. 3D projection of a confocal z-stack shows human umbilical vein endothelial cells (HUVECs) forming a functional vessel immunofluorescently stained for PECAM-1 (green) and nuclei (blue). (Wong/Searson Lab)

INBT’s science writer, Mary Spiro, interviewed device developer Andrew Wong, a doctoral student Searson’s  lab, for the NanoByte Podcast. Wong is an INBT training grant student. Listen to NANOBYTE #101 at this link.

Wong describes the transparent device, which is made up of a cylindrical channel lined with human endothelial cells and housed within a gel made of collagen, the body’s structural protein that supports living tissues. A small clump of metastatic breast cancer cells is seeded in the gel near the vessel while a nutrient rich fluid was pumped through the channel to simulate blood flow. By adding fluorescent tags the breast cancer cells, the researchers were able to track the cells’ paths over multiple days under a microscope.

VIDEO: Watch how a cancer cell approaches the artificial blood vessel, balls up and then forces its way through the endothelial cells and into the streaming fluids within the channel of the device. (Video by Searson Lab)

The lab-made device allows researchers to visualize how “a single cancer cell degrades the matrix and creates a tunnel that allows it to travel to the vessel wall,” says Wong. “The cell then balls up, and after a few days, exerts a force that disrupts the endothelial cells. It is then swept away by the flow. “

Wong said his next goal will be to use the artificial blood vessel to investigate different cancer treatment strategies, such as chemotherapeutic drugs, to find ways to improve the targeting of drug-resistant tumors.

Results of their experiments with this device were published in the journal Cancer Research in September.

Andrew Wong (left) and Peter Searson. (Photo by Will Kirk/Homewood Photography)

Andrew Wong (left) and Peter Searson. (Photo by Will Kirk/Homewood Photography)

Check out this gallery of images from the Searson Lab. The captions are as follows:
Figure 1. 3D projection of a confocal z-stack shows human umbilical vein endothelial cells (HUVECs) forming a functional vessel immunofluorescently stained for PECAM-1 (green) and nuclei (blue).
Figure 2. 3D projection of a confocal z-stack shows human umbilical vein endothelial cells (HUVECs) forming a vessel with dual-labeled MDA-MB-231 breast cancer cells on the periphery.
Figure 3. Phase-contrast and fluorescence overlays depicting a functional vessel comprised of human umbilical vein endothelial cells (HUVECs) with dual-labeled MDA-MB-231 breast cancer cells on the periphery (green in the nucleus, red in the cytoplasm).

For all press inquiries regarding INBT, its faculty and programs, contact Mary Spiro, mspiro@jhu.edu or 410-516-4802.

 

Jordan Green named to PopSci’s Brilliant Ten

Jordan Green, Johns Hopkins University associate professor of biomedical engineering and executive committee member for the Johns Hopkins Institute for NanoBioTechnology, was named one of Popular Science magazine’s Brilliant Ten. The magazine recognized “inspired young scientists and engineers … whose ideas will transform the future.”

Jordan Green (Photo by Marty Katz)

Jordan Green (Photo by Marty Katz)

Green’s work focuses on using nanoscale particles made in the shape of footballs that can train the body’s own immune system to tackle cancer cells. Turns out, particles with the elongated ovoid shape have a slightly larger surface area, which gives them an edge over spherical particles. The football-shaped particles did a better job of triggering the immune system to attack the cancer cells.

Green collaborated with Jonathan Schneck, M.D., Ph.D., professor of pathology, medicine and oncology at Johns Hopkins School of Medicine. Both are affiliated faculty members of Johns Hopkins Institute for  NanoBioTechnology. Their work was published in the journal Biomaterials on Oct 5, 2013.

Read more about their research here.

Congratulations to Dr. Green for the recognition of your interesting and promising work!

Watch a video where Green explains his work in simple terms using toys.

Three-way brain tumor therapy sparks immune system with radiation

Johns Hopkins researchers have found that combining radiation with two therapies that activate the immune system allow mice with brain tumors (glioblastoma) to survive longer than mice who did not receive the combo treatment. INBT affiliated faculty member Michael Lim, M.D., an associate professor of neurosurgery, oncology at the Johns Hopkins University School of Medicine, said the radiation may act “as kind of kindling, to try to induce an immune response.”

brainRead the full press release from Johns Hopkins regarding the publication in PLoS One journal below:

A triple therapy for glioblastoma, including two types of immunotherapy and targeted radiation, has significantly prolonged the survival of mice with these brain cancers, according to a new report by scientists at the Johns Hopkins Kimmel Cancer Center.

Mice with implanted, mouse-derived glioblastoma cells lived an average of 67 days after the triple therapy, compared with mice that lasted 24 days when they received only the two immunotherapies. Half of the mice who received the triple therapy lived 100 days or more and were protected against further tumors when new cancer cells were re-injected under the animals’ skins.

The combination treatment described in the July 11 issue of PLOS One consists of highly focused radiation therapy targeted specifically to the tumor and strategies that lift the brakes and activate the body’s immune system, allowing anti-cancer drugs to attack the tumor. One of the immunotherapies is an antibody that binds to and blocks an immune checkpoint molecule on T cells called CTLA-4, allowing the T-cells to infiltrate and fight tumor cells. The second immunotherapy, known as 4-1BB, supplies a positive “go” signal, stimulating anti-tumor T cells.

None of the treatments are new, but were used by the Johns Hopkins team to demonstrate the value of combining treatments that augment the immune response against glioblastomas, the most common brain tumors in human adults. The prognosis is generally poor, even with early treatment.

“We’re trying to find that optimal balance between pushing and pulling the immune system to kill cancer,” said Charles Drake, M.D., Ph.D., an associate professor of oncology, immunology and urology, and medical oncologist at the Johns Hopkins Kimmel Cancer Center.

The researchers speculate that when radiation destroys tumor cells, the dead tumor cells may release proteins that help train immune cells to recognize and attack the cancer, said Michael Lim, M.D., an associate professor of neurosurgery, oncology at the Johns Hopkins University School of Medicine and member of Johns Hopkins’ Institute of NanoBiotechnology.

“Traditionally, radiation is used as a definitive therapy to directly kill cancer cells,” said Lim, who also serves as director of the Brain Tumor Immunotherapy Program and director of the Metastatic Brain Tumor Center at Johns Hopkins Medicine. “But in this situation we’re using radiation as kind of kindling, to try to induce an immune response.”

Lim says if further studies affirm the value of the triple therapy in animals and humans, the radiation could be delivered a few days before or after the immunotherapies and still achieve the same results. Lim said this leeway “could make applications of this therapy in patients possible.”

The researchers say they were also encouraged to see that the triple therapy created “immune memory” in mice that were long-term survivors. When brain tumor cells were re-introduced under the skin of the animals, their immune systems appeared to protect them against the development of a new brain tumor.

Drake said since the immune system usually doesn’t generate a memory when foreign (tumor) cells are still present in the body. “But the idea that this combination treatment was successful at generating immunological memory really suggests that we could do this in patients and generate some long-term responses.”

The researchers are developing a variety of clinical trials to test combination therapies against brain tumors.

Other researchers on the study include Zineb Belcaid, Jillian A. Phallen, Alfred P. See, Dimitrios Mathios, Chelsea Gottschalk, Sarah Nicholas, Meghan Kellett, Jacob Ruzevick, Christopher Jackson, Xiaobu Ye, Betty Tyler, and Henry Brem of the Department of Neurosurgery at Johns Hopkins University School of Medicine; Jing Zeng, Phuoc T. Tran, and John W. Wong of the Department of Radiation Oncology and Molecular Radiation Sciences at the Johns Hopkins Kimmel Cancer Center;  and Emilia Albesiano, Nicholas M. Durham, and Drew M. Pardoll at the Kimmel Center’s Department of Oncology and Medicine, Division of Immunology.

Funding for the study was provided by the WW Smith Charitable Foundation and individual patient donations.

Michael Lim is a consultant for Accuray and receives research funding from Accuray, Bristol-Meyers Squibb, Celldex and Aegenus. Charles Drake has served as a consultant for Amplimmune, Bristol-Meyers Squibb, Compugen, Dendreon, ImmunExcite and Roche/Genentech and is on the Scientific Advisory Board of Compugen. He receives research funding from Bristol-Meyers Squibb, Aduro and Janssen and has stock ownership in Compugen. Drew Pardoll is a consultant/advisor for Jounce Therapeutics, Bristol-Meyers Squibb, ImmuneXcite and Aduro and receives research funding from Bristol-Meyers Squibb. Jing Zeng, Michael Lim, Charles Drake and Drew Pardoll hold a patent for the work related to this study.

The authors declare that they have a patent relating to material pertinent to this article; this international patent application (PCT/US2012/043124) is entitled “Use of Adjuvant Focused Radiation Including Stereotactic Radiosurgery for Augmenting Immune Based Therapies Against Neoplasms.” These relationships are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

For all press inquiries regarding INBT, its faculty and programs, contact Mary Spiro, mspiro@jhu.edu or 410-516-4802.

From bacterial intelligence to a cyber-war on cancer

Screen Shot 2014-03-18 at 11.40.42 AMINBT will host a special seminar, “From bacterial intelligence to a cyber-war on cancer,” on April 17 at 2 p.m. in Room 160 of the Mattin Center. The guest speaker is Eshel Ben-Jacob, PhD, professor and Maguy-Glass Chair in Physics of Complex Systems from Tel Aviv University. This event is free and open to the university community.

ABSTRACT: Cancer continues to elude us. Metastasis, relapse and drug resistance are all still poorly understood and clinically insuperable. Evidently, the prevailing paradigms need to be re-examined and out-of-the-box ideas ought to be explored. Drawing upon recent discoveries demonstrating the parallels between collective behaviors of bacteria and cancer, Dr. Ben-Jacob shall present a new picture of cancer as a society of smart communicating cells motivated by the realization of bacterial social intelligence. There is growing evidence that cancer cells, much like bacteria, rely on advanced communication, social networking and cooperation to grow, spread within the body, colonize new organs, relapse and develop drug resistance. Dr. Ben-Jacob shall address the role of communication, cooperation and decision-making in bacterial collective navigation, swarming logistics and colony development. This will lead to a new picture of cancer as a networked society of smart cells and to new understanding of the interplay between cancer and the immune system. Dr. Ben-Jacob shall reason that the new understanding calls for “a cyber-war” on cancer – the developments of drugs to target cancer communication and control.

Related Links:

Bacterial linguistic communication and social intelligence

Bacterial survival strategies suggest rethinking cancer cooperativity

 

 

Cancer spreads through ‘Rock’ and ‘Rho’

n low oxygen conditions, breast cancer cells form structures that facilitate movement, such as filaments that allow the cell to contract (green) and cellular ‘hands’ that grab surfaces to pull the cell along (red). Credit: Daniele Gilkes

In low oxygen conditions, breast cancer cells form structures that facilitate movement, such as filaments that allow the cell to contract (green) and cellular ‘hands’ that grab surfaces to pull the cell along (red).
Credit: Daniele Gilkes

ROCK1 and RhoA genes found partly to blame for cancer metastasis. Gregg Semenza, co-director of the Johns Hopkins Physical Sciences-Oncology Center (PS-OC), led a team that made the discovery. The following comes from a Johns Hopkins press release:

Biologists at The Johns Hopkins University have discovered that low oxygen conditions, which often persist inside tumors, are sufficient to initiate a molecular chain of events that transforms breast cancer cells from being rigid and stationary to mobile and invasive. Their evidence, published online in Proceedings of the National Academy of Sciences on Dec. 9, underlines the importance of hypoxia-inducible factors in promoting breast cancer metastasis.

“High levels of RhoA and ROCK1 were known to worsen outcomes for breast cancer patients by endowing cancer cells with the ability to move, but the trigger for their production was a mystery,” says Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Medicine at the Johns Hopkins University School of Medicine and senior author of the article. “We now know that the production of these proteins increases dramatically when breast cancer cells are exposed to low oxygen conditions.”

To move, cancer cells must make many changes to their internal structures, Semenza says. Thin, parallel filaments form throughout the cells, allowing them to contract and cellular “hands” arise, allowing cells to “grab” external surfaces to pull themselves along. The proteins RhoA and ROCK1 are known to be central to the formation of these structures.

Moreover, the genes that code for RhoA and ROCK1 were known to be turned on at high levels in human cells from metastatic breast cancers. In a few cases, those increased levels could be traced back to a genetic error in a protein that controls them, but not in most. This activity, said Semenza, led him and his team to search for another cause for their high levels.

What the study showed is that low oxygen conditions, which are frequently present in breast cancers, serve as the trigger to increase the production of RhoA and ROCK1 through the action of hypoxia-inducible factors.

“As tumor cells multiply, the interior of the tumor begins to run out of oxygen because it isn’t being fed by blood vessels,” explains Semenza. “The lack of oxygen activates the hypoxia-inducible factors, which are master control proteins that switch on many genes that help cells adapt to the scarcity of oxygen.” He explains that, while these responses are essential for life, hypoxia-inducible factors also turn on genes that help cancer cells escape from the oxygen-starved tumor by invading blood vessels, through which they spread to other parts of the body.

Daniele Gilkes, Ph.D., a postdoctoral fellow at the PS-OC and lead author of the report, analyzed human metastatic breast cancer cells grown in low oxygen conditions in the laboratory. She found that the cells were much more mobile in the presence of low levels of oxygen than at physiologically normal levels. They had three times as many filaments and many more “hands” per cell. When the hypoxia-inducible factor protein levels were knocked down, though, the tumor cells hardly moved at all. The numbers of filaments and “hands” in the cells and their ability to contract were also decreased.

When Gilkes measured the levels of the RhoA and ROCK1 proteins, she saw a big increase in the levels of both proteins in cells grown in low oxygen. When the breast cancer cells were modified to knock down the amount of hypoxia-inducible factors, however, the levels of RhoA and ROCK1 were decreased, indicating a direct relationship between the two sets of proteins. Further experiments confirmed that hypoxia-inducible factors actually bind to the RhoA and ROCK1 genes to turn them on.

The team then took advantage of a database that allowed them to ask whether having RhoA and ROCK1 genes turned on in breast cancer cells affected patient survival. They found that women with high levels of RhoA or ROCK1, and especially those women with high levels of both, were much more likely to die of breast cancer than those with low levels.

“We have successfully decreased the mobility of breast cancer cells in the lab by using genetic tricks to knock the hypoxia-inducible factors down,” says Gilkes. “Now that we understand the mechanism at play, we hope that clinical trials will be performed to test whether drugs that inhibit hypoxia-inducible factors will have the double effect of blocking production of RhoA and ROCK1 and preventing metastases in women with breast cancer.”

Other authors of the report include Lisha Xiang, Sun Joo Lee, Pallavi Chaturvedi, Maimon Hubbi and Denis Wirtz of the Johns Hopkins University School of Medicine.

This work was supported by grants from the National Cancer Institute (U54-CA143868), the Johns Hopkins Institute for Cell Engineering, the American Cancer Society and the Susan G. Komen Breast Cancer Foundation.

Picture this: Transcription ‘twists’ toward metastasis

Mol Cancer Res Cover (1)

Molecular Cancer Research Cover

Researchers associated with Johns Hopkins Physical Sciences-Oncology Center, Johns Hopkins School of Medicine and School of Public Health have published “The Twist Box Domain Is Required for Twist1-induced Prostate Cancer Metastasis,” in a recent issue of the journal Molecular Cancer Research. An illustration related to the work graced the cover.

Authors on the paper include co-lead authors Rajendra P. Gajula and Sivarajan T. Chettiar,  as well as Russell D. Williams, Saravanan Thiyagarajan, Yoshinori Kato, Khaled Aziz, Ruoqi Wang, Nishant Gandhi, Aaron T. Wild, Farhad Vesuna, Jinfang Ma, Tarek Salih, Jessica Cades, Elana Fertig, Shyam Biswal, Timothy F. Burns, Christine H. Chung, Charles M. Rudin, Joseph M. Herman, Russell K. Hales, Venu Raman, Steven S. An and corresponding author Phuoc T. Tran

Here is an abstract of their paper and caption for the cover:

“Twist1 plays key roles during development and is a master transcriptional regulator of the epithelial-mesenchymal transition that promotes cancer metastasis. We demonstrated three important findings in prostate cancer cells that overexpress Twist1: (1) Twist1 leads to elevated cytoskeletal stiffness and traction forces at the migratory edge of cell collections; (2) The Twist box domain is required for Twist1-induced pro-metastatic in vitro properties and in vivo metastases; and (3) Hoxa9 is a novel Twist1 transcriptional target that is required for Twist1-induced pro-metastatic phenotypes. Targeting the Twist box domain and Hoxa9 may effectively limit prostate cancer metastatic potential.”

Visit the journal here: Molecular Cancer Research 

 

Veltri presents PS-OC hosted talk on digital pathology and prostate cancer

Robert Veltri, associate professor Of Urology and Oncology at the Johns Hopkins School of Medicine and Director of the Fisher Biomarker Biorepository Laboratory, will  present the talk Quantitative Histomorphometry of Digital Pathology: Case study in prostate cancer,” to members of the Denis Wirtz Lab and the Johns Hopkins Physical Sciences-Oncology Center on Monday, December 9 at 2 p.m. in Croft G40 on the Homewood campus. Seating is limited.

veltri

Robert Veltri

Veltri studies the biomarkers for prostate and bladder cancer and is collaborating on applications of Quantitative Digital Image Analysis (QDIA) using microscopy to quantify nuclear structure and tissue architecture. Collaborations include Case Western Reserve University biomedical engineering and the University of Pittsburgh Electrical Engineering departments studying to assess cancer aggressiveness in prostate cancer (PCa). Furthermore,  he is studying the application of molecular biomarkers for prostate (CaP) and bladder cancer (BlCa) detection and prognosis. Veltri’s work is funded by the National Cancer Institute’s PS-OC program grant), Early Detection Research Network (EDRN), and the Department of Defense related to research on Active Surveillance for PCa. He is also a co-investigator on a SBIR-I and II grant studying the application of microtransponders to multiplex molecular urine and serum biomarker testing for CaP.  Veltri has authored over 152 scientific publications and is either inventor or co-inventor on over twenty patents and two trademarks.

In cancer fight, one sportsball-shaped particle works better than another

Apparently in the quest to treat or cure cancer, football trumps basketball. Research from the laboratory of Jordan Green, Ph.D., assistant professor of biomedical engineering at the Johns Hopkins University School of Medicine, has shown that elliptical football-shaped microparticles do a better job than basketball-shaped ones in triggering an immune response that attacks cancer cells.

football particles-greenGreen collaborated with Jonathan Schneck, M.D., Ph.D., professor of pathology, medicine and oncology. Both are affiliated faculty members of Johns Hopkins Institute for NanoBioTechnology. Their work was published in the journal Biomaterials on Oct 5.

The particles, which are essentially artificial antigen presenting cells (APCs), are dotted with tumor proteins (antigens) that signal trouble to the immune response. It turns out that flattening the spherical particles into more elliptical, football-like shapes provides more opportunities for the fabricated APCs to come into contact with cells, which helps initiate a stronger immune response.

If you think about it, this makes sense. You can’t tackle someone on the basketball court the way you can on the gridiron.

Read the Johns Hopkins press release here:

FOOTBALL-SHAPED PARTICLES BOLSTER THE BODY’S DEFENSE AGAINST CANCER

Read the journal article here:

Particle shape dependence of CD8+ T cell activation by artificial antigen presenting cells

ChemBE seminar focuses on cancer research innovation

The Department of Chemical and Biomolecular Engineering’s  scheduled Thursday, October 10 seminar will continue as planned at 3:30 PM in Maryland Hall 110. Jerry Lee, the Health Sciences Director at the National Cancer Institute (National Institutes of Health) will present his lecture “Advancing Convergence and Innovation in Cancer Research: National Cancer Institute Center for Strategic Scientific Initiatives (CSSI).”  A small reception will follow in Maryland Hall 109.

Jerry Lee

Jerry S.H. Lee, Ph.D

ABSTRACT

The National Cancer Institute (NCI) Center for Strategic Scientific Initiatives (CSSI) is a component of the NCI’s Office of the Director focused on emerging advanced technologies that have the potential of uniquely impacting the full spectrum of cancer basic and clinical research. The Center is tasked with planning, developing, executing, and implementing rapid strategic scientific and technology initiatives that keep the Institute ahead of the scientific curve with respect to potential new exciting areas and discoveries. This may involve direct development and application of advanced technologies, synergy of large scale and individual initiated research, and/or using available federal mechanisms to forge novel partnerships that emphasize innovation, trans-disciplinary teams and convergence of scientific disciplines. With an emphasis on complementing the scientific efforts of other NCI divisions, CSSI’s efforts seek to enable the translation of discoveries into new interventions, both domestically and in the international arena, to detect, prevent and treat cancer more effectively. This presentation will highlight various programs and their associated accomplishments within CSSI’s broad scientific portfolio of programs (Clinical Proteomic Tumor Analysis Consortium, Alliance for Nanotechnology in Cancer, Physical Sciences-Oncology Centers, Innovative Molecular Analysis Technologies, and Provocative Questions) and describe future directions and opportunities.

Game Theory and Cancer

What does game theory and cancer have to do with each other. I am not sure but this interesting workshop hosted by the Princeton Physical Sciences-Oncology Center and Johns Hopkins University might help you figure that out.

An announcement about the event reads:

Screen Shot 2013-08-02 at 12.03.06 PMRegistration is now open for the Workshop on Game Theory and Cancer, scheduled on August 12-13 in Baltimore, MD, and jointly hosted by our Princeton PS-OC and Johns Hopkins University. The main goal of this workshop is to provide a dialogue between leading basic researchers and clinical investigators that would help make headway against the very stubborn problem of cancer, and to jolt the oncology community into confronting the serious clinical problems that have previously been avoided.

The flyer is pretty cool, too.  Check it out here.

Additional information and preliminary agenda can be found at: http://www.princeton.edu/psoc/training/

To register, please go to: https://prism.princeton.edu/ps-oc/regform.php

For questions about the event, email maranzam@princeton.edu or sclam@princeton.edu