Betenbaugh research seeks better control of antibody production

Antibodies are blood proteins created by the immune system in response to a certain antigen. Antibodies have become the chief component in myriad medicine applications from diagnostic tests to several widely used pharmaceuticals for the treatment of asthma, arthritis, cancer and more.

How handy would it be to be able control the function of the antibodies made in a lab, simply by tweaking the nutrient media that you used to grown them in? And how useful would it be, if you could increase the quantity of antibodies produced, also be modifying the media in which they were created?

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Bound for destruction: Y-shapted antibody binds t-cell and macrophage to tumor cell.

Pharmaceutical manufacturers seek more efficient ways to grow genetically engineered human antibodies on a large scale. Through a partnership with MedImmune, researchers in the laboratory of Michael Betenbaugh are taking an engineering approach to the solution. Betenbaugh, professor of Chemical and Biomolecular Engineering and an affiliate of Johns Hopkins INBT, seeks to discover ways to improve the growth media for the antibody-producing microbes. Their lab is not only looking at more efficient ways to grow large quantities of antibodies via microbes but also to find out if the properties of the antibodies can be influenced by the properties of the media in which the microbes are grown.

To read more about this research and the partnership with MedImmune, visit this link.

http://ventures.jhu.edu/johns-hopkins-medimmune-partnership-examines-antibody-production-house-looks-to-make-it-more-efficient/

MedImmune drug delivery expert to talk

Johns Hopkins Institute for NanoBioTechnology hosts Anand Subramony of MedImmune, who will present a one-house lecture/seminar on Friday, November 18 at 10:30 a.m. in the Great Hall in Levering Hall on the Homewood campus. Subramony is  Vice President for Drug Delivery and Device Development at MedImmune and will discuss the development of novel patient centric injection devices and novel drug delivery technologies for local delivery.

Dr. Sumbramony is an expert in materials science for drug delivery. He earned his PhD in Chemistry, Solid State Materials Science from Purdue University.  He has worked as a principal scientist for Johnson & Johnson and was the principal fellow and head of novel drug delivery technologies and therapeutics at Novartis Institutes for Biomedical Research, Inc. His research goals include developing next generation platform drug delivery devices for patient centric delivery of monoclonal antibodies, proteins, and peptides.

Anand Subramony of MedImmune

Anand Subramony of MedImmune

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The talk is free and open to the entire Johns Hopkins community. RSVP to Camille Mathis by emailing her at cmathis@jhu.edu.

 

Undergraduate symposium showcases multidisciplinary research

Undergraduate students affiliated with Johns Hopkins Institute for NanoBioTechnology (INBT) laboratories hosted their annual research symposium on Nov 10 at the Homewood campus. Five students gave oral presentations and 30 students presented posters during the half-day event designed to showcase multidisciplinary work from across INBT affiliated laboratories.

Winners Allie Zito, Joey Li and Hayley Strasburger

Symposium winners Allie Zito, Joey Li and Hayley Strasburger.

Talks were given during the first part of the symposium. Oral presenters included Damian Cross and Aseem Jain, who shared a talk about Perileve: A novel method for refractory ascites; James Shamul, who spoke about a Novel Micellar Drug Delivery System using Poly (Beta-amino ester)-Poly (ethylene glycol) copolymer; Michael Pozin, who presented Heat Transfer Modeling for Femoroplasty Procedure; and Hayley Strasburger, who described how Noggin inhibits bmp signaling in oligodendrocytes progenitor cells to repress trans-differentiation into astrocytes.

During the second half of the symposium, poster presenters talked to volunteer judges comprised of INBT staff and alumni. There were three poster categories: concept, overall and crowd favorite. While the volunteer judges evaluated the first two groups, crowd favorite was voted on by every attendee by texting a poster number to a certain phone number. Winners included in the Concept category Victor Tang (1st) and Allie Zito (2nd). In the overall category, Hayley Strasburger (1st) and Joey Li (2nd) were the inners. Allie Zito also won crowd favorite.

15000596_10154704353192277_9071690777271476868_oThe event was funded by the Office of the Provost and given organizational support by INBT. Thanks and acknowledgement to everyone who came out to the symposium, to the judges who took time away from their work to provide feedback, the Office of the Provost for funding the event and to INBT, especially Camille Mathis, Ellie Boettinger-Heasley, Tom Fekete, and Gregg Nass.

 

 

 

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Undergraduate symposium showcases ‘frontiers in medicine’

Johns Hopkins Institute for Nanobiotechnollgy’s Undergraduate Research Symposium, presented by the INBT Undergraduate Research Leadership, is scheduled for Thursday, November 10 from noon to 5 p.m. in the Glass Pavilion on the Homewood campus. The theme of the symposium is Frontiers in Medicine: Biological and Engineering Research. The event features invited student speaker talks, a poster session, an awards ceremony and light lunch.

Student Talks include the following: James Shamul, “Novel Micellar Drug Delivery System Using Poly(β-amino ester)–Poly(ethylene glycol) Copolymer;” Damian Cross, “Perileve: A Novel Management Method for Refractory Ascites;”Hayley Strasburger, “Noggin inhibits bmp signaling in oligodendrocyte progenitor cells to repress transdifferentiation into astrocytes; and Michael Pozin, “Heat Transfer Modeling for Femoroplasty Procedure.”

Please direct any questions to inbt.undergrads@gmail.com.

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INBT’S undergraduate research symposium is Nov 10 in the Glass Pavilion

Agenda

12:00 pm: Check in
12:45 pm: Welcome
1:00 pm: Student Talks
2:00 pm: 1st Poster Session
3:15 pm: 2nd Poster Session
4:30 pm: Awards

 

 

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Nanofiber technology rebuilds soft tissue damage

Patients with soft tissue damage will experience dramatic improvements with LifeSprout Tissue Regenerative Matrix (TRM). Hai-Quan Mao (Professor, MSE/INBT ChemBE), collaborating with Johns Hopkins School of Medicine faculty specialists Justin Sacks and Sashank Reddy, developed the technology that combines a tissue-plumping hydrogel with a cell-supporting nanofiber framework. Resulting tissue repairs are individualized and have a reduced chance of scarring, as well as being scar and inflammation free. The Louis B. Thalheimer Funds grant, among other funds, will help move LifeSprout TRM from prototype to pre-clinical testing and FDA approval.

 Nanofibers expand to fill the space left behind by tissue damage.

Nanofibers expand to fill the space left behind by tissue damage.

Often it takes years to bring a new technology through the approval process from bench top to bedside. However, because this technology uses materials that have been previously approved by the FDA, the time to clinical use should be shortened.

Watch this video by Johns Hopkins video storyteller Renee Fischer on LifeSprout Tissue Regenerative Matrix. Read more about the technology here on the Rising To the Challenge website.

Cell Dynamics in Health and Disease symposium

Screen Shot 2016-10-25 at 5.38.43 PMThe Institute for Basic Biomedical Sciences, Center for Cell Dynamics at the Johns Hopkins School of Medicine presents the symposium “Cell Dynamics in Health and Disease” on Thursday, November 17 from 9 a.m. to 5:30 p.m. in the Mountcastle Auditorium located in the Preclinical Teaching Building, 725 N. Wolfe Street on the medical campus.  The program includes invited faculty and guest expert speakers followed by a wine and cheese poster session.

The full agenda, which includes speakers from Harvard Medical School, UC-San Francisco, New York University, University of Pennsylvania, as well as Johns Hopkins University School of Medicine, can be viewed here.

Highlighted talks include the following:

  • 9:20 AM Opening Keynote Speaker
    “Physiology and Pharmacology of Microtubule Dynamics”
    Tim Mitchison, PhD
    Hasib Sabbagh Professor of Systems Biology
    Harvard Medical School
  • 10:45 AM “Regulation of RNA granule dynamics by intrinsically disordered proteins”
    Geraldine Seydoux, PhD
    Sheldon Professor in Medical Discover
    Department of Molecular Biology and Genetics
    Johns Hopkins University School of Medicine
  • 11:15 AM “Reverse Engineering Polarity Network Wiring”
    Lani Wu, PhD
    Professor
    Department of Pharmaceutical Chemistry
    University California, San Francisco
  • 11:45 AM “Toward Total Synthesis of Cell Function and Its Biomedical Applications”
    Takanari Inoue, PhD
    Associate Professor
    Department of Pharmacology and Molecular Sciences
    Department of Biological Chemistry and Biomedical Engineering
    Center for Cell Dynamics
    Johns Hopkins University School of Medicine
  • 1:15 PM “Microtubule Mechanics in the Beating Heart”
    Ben Prosser, PhD
    Assistant Professor
    Department of Physiology
    University of Pennsylvania
  • 1:45 PM “How Cells Count: Molecular Control of Centriole Duplication”
    Andrew Holland, PhD
    Assistant Professor
    Department of Molecular Biology and Genetics
    Johns Hopkins University School of Medicine
  • 2:15 PM “Cellular and Molecular Forces That Drive Metastases”
    Andrew Ewald, PhD
    Associate Professor
    Department of Cell Biology
    Center for Cell Dynamics
    Johns Hopkins University School of Medicine
  • 3:15 PM Closing Keynote Speaker
    “Forming the Next Generation”
    Ruth Lehman, PhDAkshay
    Director
    Skirball Institute
    Professor
    Department of Cell Biology
    New York University

Registration is required at this link and early registrants receive a souvenir Center for Cell Dynamics t-shirt, while supplies last. Poster submissions may also be submitted on the registration form. The t-shirt design is shown here!

Nanofiber coating prevents infections on prosthetic joints

One challenge with surgical implants is the risk of bacterial infection. Now researchers from Johns Hopkins Institute for NanoBioTechnology and the Johns Hopkins School of Medicine have developed a nano fiber coating that may help solve this problem. 

READ MORE FROM THE SCHOOL OF MEDICINE PRESS RELEASE BELOW.

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A titanium implant (blue) without a nanofiber coating in the femur of a mouse. Bacteria are shown in red and responding immune cells in yellow. Credit: Lloyd Miller/Johns Hopkins Medicine

In a proof-of-concept study on mice, scientists at The Johns Hopkins University show that a novel coating they made with antibiotic-releasing nanofibers has the potential to better prevent at least some serious bacterial infections related to total joint replacement surgery.

A report on the study, published online the week of Oct. 24 in Proceedings of the National Academy of Sciences, was conducted on the rodents’ knee joints, but, the researchers say, the technology would have “broad applicability” in the use of orthopaedic prostheses, such as hip and knee total joint replacements, as well pacemakers, stents and other implantable medical devices. In contrast to other coatings in development, the researchers report the new material can release multiple antibiotics in a strategically timed way for an optimal effect.

“We can potentially coat any metallic implant that we put into patients, from prosthetic joints, rods, screws and plates to pacemakers, implantable defibrillators and dental hardware,” says co-senior study author Lloyd S. Miller, M.D., Ph.D., an associate professor of dermatology and orthopaedic surgery at the Johns Hopkins University School of Medicine.

Surgeons and biomedical engineers have for years looked for better ways —including antibiotic coatings — to reduce the risk of infections that are a known complication of implanting artificial hip, knee and shoulder joints.

Every year in the U.S., an estimated 1 to 2 percent of the more than 1 million hip and knee replacement surgeries are followed by infections linked to the formation of biofilms — layers of bacteria that adhere to a surface, forming a dense, impenetrable matrix of proteins, sugars and DNA. Immediately after surgery, an acute infection causes swelling and redness that can often be treated with intravenous antibiotics. But in some people, low-grade chronic infections can last for months, causing bone loss that leads to implant loosening and ultimately failure of the new prosthesis. These infections are very difficult to treat and, in many cases of chronic infection, prostheses must be removed and patients placed on long courses of antibiotics before a new prosthesis can be implanted. The cost per patient often exceeds $100,000 to treat a biofilm-associated prosthesis infection, Miller says.

Major downsides to existing options for local antibiotic delivery, such as antibiotic-loaded cement, beads, spacers or powder, during the implantation of medical devices are that they can typically only deliver one antibiotic at a time and the release rate is not well-controlled. To develop a better approach that addresses those problems, Miller teamed up with Hai-Quan Mao, Ph.D., a professor of materials science and engineering at the Johns Hopkins University Whiting School of Engineering, and a member of the Institute for NanoBioTechnology, Whitaker Biomedical Engineering Institute and Translational Tissue Engineering Center.

Over three years, the team focused on designing a thin, biodegradable plastic coating that could release multiple antibiotics at desired rates. This coating is composed of a nanofiber mesh embedded in a thin film; both components are made of polymers used for degradable sutures.

To test the technology’s ability to prevent infection, the researchers loaded the nanofiber coating with the antibiotic rifampin in combination with one of three other antibiotics: vancomycin, daptomycin or linezolid. “Rifampin has excellent anti-biofilm activity but cannot be used alone because bacteria would rapidly develop resistance,” says Miller. The coatings released vancomycin, daptomycin or linezolid for seven to 14 days and rifampin over three to five days. “We were able to deploy two antibiotics against potential infection while ensuring rifampin was never present as a single agent,” Miller says.

The team then used each combination to coat titanium Kirschner wires — a type of pin used in orthopaedic surgery to fix bone in place after wrist fractures — inserted them into the knee joints of anesthetized mice and introduced a strain of Staphylococcus aureus, a bacterium that commonly causes biofilm-associated infections in orthopaedic surgeries. The bacteria were engineered to give off light, allowing the researchers to noninvasively track infection over time.

Miller says that after 14 days of infection in mice that received an antibiotic-free coating on the pins, all of the mice had abundant bacteria in the infected tissue around the knee joint, and 80 percent had bacteria on the surface of the implant. In contrast, after the same time period in mice that received pins with either linezolid-rifampin or daptomycin-rifampin coating, none of the mice had detectable bacteria either on the implants or in the surrounding tissue.

“We were able to completely eradicate infection with this coating,” says Miller. “Most other approaches only decrease the number of bacteria but don’t generally or reliably prevent infections.”

After the two-week test, each of the rodents’ joints and adjacent bones were removed for further study. Miller and Mao found that not only had infection been prevented, but the bone loss often seen near infected joints — which creates the prosthetic loosening in patients — had also been completely avoided in animals that received pins with the antibiotic-loaded coating.

Miller emphasized that further research is needed to test the efficacy and safety of the coating in humans, and in sorting out which patients would best benefit from the coating — people with a previous prosthesis joint infection receiving a new replacement joint, for example.

The polymers they used to generate the nanofiber coating have already been used in many approved devices by the U.S. Food and Drug Administration, such as degradable sutures, bone plates and drug delivery systems.

In addition to Miller and Mao, the study’s authors are Alyssa Ashbaugh, Xuesong Jiang, Jesse Zheng, Andrew Tsai, Woo-Shin Kim, John Thompson, Robert Miller, Jonathan Shahbazian, Yu Wang, Carly Dillen, Alvaro Ordonez, Yong Chang, Sanjay Jain, Lynne Jones and Robert Sterling of The Johns Hopkins University.

Funding for this work was provided by a Nexus Award from the Johns Hopkins Institute for Clinical and Translational Research, which has been funded by the National Center for Advancing Translational Sciences and the National Institutes of Health Roadmap for Medical Research.

by Shawna Williams, shawna@jhmi.edu and Lauren Nelson, laurennelson@jhmi.edu

For press inquiries related to INBT, contact Mary Spiro, mspiro@jhu.edu

NCI grant establishes center to advance cancer curing goals

The National Cancer Institute has awarded Johns Hopkins Institute for NanoBioTechnology (INBT) a $9 million grant to support a multidisciplinary center to discover news ways to diagnose and treat cancer. NCI, which is part of the National Institutes for Health, allocated the funds over five years to enable scholars in the Johns Hopkins Physical Sciences-Oncology center to apply the tools of the physical scientist, engineer, applied mathematician, cancer biologist and others to unravel how cancer cells survive, grow and migrate.

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Artist’s image of a cancer cell traveling through a 3D matrix that closely resembles the environment through which cancer cells move in a human body. IMAGE CREDIT: JENNIFER E. FAIRMAN / DEPARTMENT OF ART AS APPLIED TO MEDICINE

The PS-OC is comprised of researchers from university’s Whiting School of Engineering and its School of Medicine, as well as collaborators from Washington University in Saint Louis, the University of Pennsylvania Abramson Cancer Center, and the University of Arizona comprise the new center based within INBT.

Denis Wirtz—the university’s vice provost for research, INBT’s associate director, professor in the Department of Chemical and Biomolecular Engineering, and a member of the Johns Hopkins Kimmel Cancer Center—will serve as director and principal investigator of the new center.

“Instead of looking at other aspects like tumor growth, I’ll be working with my colleagues in the schools of engineering and medicine to uncover the physical underpinnings of cancer metastasis,” Wirtz said. “The ‘team science’ approach in our center should result in the creation of new therapies targeting metastasis, the primary cause of human cancer deaths.”

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Denis Wirtz

Kenneth Pienta, professor of urology, oncology, and pharmacology and molecular sciences at the Johns Hopkins School of Medicine, will serve as the PS-OC’s associate director. Pienta also co-directs Johns Hopkins University inHealth Signature Initiative, a trans-University, and cross-disciplinary effort to coordinate and apply the intelligent use of population health data for individual patients. Currently, his research involves defining tumor microenvironments and how they contribute to the growth of tumors and the spread of cancer. His bench laboratory program is closely tied to the development of novel therapies for prostate cancer.

Ed Schlesinger, dean of the university’s Whiting School of Engineering, endorses Wirtz’s strategy. “By approaching the problem of metastasis from an engineering perspective,” Schlesinger said, “Denis has provided an entirely new understanding of cell motility and has opened the doors to the possibility of new and far more effective cancer treatments.”

This is not the first PS-OC for INBT. Wirtz directed INBT’s first 5-year PS-OC grant, which ran from the fall of 2009 until 2014. This new PS-OC grant creates a brand new center, with projects that have evolved out of the first center’s original research goals. The new center projects include:

  • The Role of Physical Cues in Collective Cell Invasion – This project will examine how the physical forces exerted upon cancer cells when they are confined within a tumor can affect the migration of these cells, both collectively and individually. The team is led by Konstantinos Konstantopoulos, chair of the university’s Department of Chemical and Biomolecular Engineering.
  • Forces Involved in Collective Cell Migration – When they break away from a tumor, some cancer cells seem to prefer to travel in groups. This team, led by center director Wirtz, will study the forces involved in organizing the collective migration of breast cancer cells in both 2D and 3D environments.
  • Impact of low oxygen on the migration of sarcoma cells – Low oxygen within a tumor (hypoxia) dramatically increases pulmonary metastasis and results in poor health outcomes. Researchers led by Sharon Gerecht, a professor of chemical and biomolecular engineering, will try to determine how primary tumor cells respond to oxygen in their microenvironment. The goal is to better understand the spread of cancer and identify new treatment targets.
Dr. Ken Pienta lab coat

Ken Pienta

Other members of the Johns Hopkins PS-OC center include Andy Ewald and Daniele Gilkes of the School of Medicine, Pei-Hsun Wu and Sean X. Sun of the Whiting School of Engineering, Karin Eisinger and Celeste Simon of the University of Pennsylvania, and Charles Wolgemuth of the University of Arizona.

The Hopkins center is part of a nation-wide NCI Physical Sciences-Oncology Network.

“As a complement to traditional cancer research approaches, the innovative trans-disciplinary approaches and perspectives in the PS-ON will aid in unraveling the complexity of cancer,” said Nastaran Kuhn, associate director of NCI’s Division of Cancer Biology PS-ON program. “These approaches are aimed at understanding the mechanistic underpinnings of cancer progression and ultimately developing effective cancer therapies.”

 

 

Gerecht and Mao named new INBT leadership

Leadership duties for Johns Hopkins Institute for NanoBioTechnology (INBT) will pass to professors Sharon Gerecht and Hai-Quan Mao of the Whiting School of Engineering, effective January 1, 2017. Gerecht will serve as Director and Mao will serve as Associate Director. Current INBT director, Peter Searson of the Department of Materials Science and Engineering, and Associate Director, Denis Wirtz, the University’s Vice Provost for Research and Theophilus H. Smoot Professor in the Department of Chemical and Biomolecular Engineering, will step down after 10 years; they will remain at Hopkins.

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Sharon Gerecht, Hai-Quan Mao will lead INBT effective Jan. 1, 2017.

“Both Sharon and Hai-Quan embrace INBT’s original vision, which seeks to bring together researchers from diverse disciplines to solve problems at the interface of nanotechnology and medicine,” said INBT’s founding director Peter Searson and Joseph R. and Lynn P. Reynolds Professor. “Their contributions to multidisciplinary research, commitment to technology transfer, and vision in educating the next generation of leaders in nanobiotechnology made Sharon and Hai-Quan ideal candidates for the job. Denis and I are delighted to pass the baton to two outstanding faculty members who both have a remarkable track record of innovation and translation.”

Gerecht, the Kent Gordon Croft Investment Faculty Scholar, is a professor in the Department of Chemical and Biomolecular Engineering. Her research focuses on ways to control the fate of stem cells, which are the most fundamental building blocks of tissues and organs. She was the inaugural winner of the University President’s Frontier Award.

Mao is a professor in the departments of Materials Science and Engineering and Biomedical Engineering, and currently holds a joint appointment in the Translational Tissue Engineering Center at Johns Hopkins School of Medicine. His research is focused on engineering novel nano-structured materials for nerve regeneration and therapeutic delivery. He won the University’s 2015 Cohen Translational Engineering Award and a 2015 University Discovery Award.

“Since its inception, INBT has been a leader in cross-divisional research at Johns Hopkins. Under Sharon and Hai-Quan’s leadership will further the institute’s mission to advance research and education at the intersection of engineering, medicine, and health.” said Whiting School dean Ed Schlesinger.

INBT was launched in May 2006, with $4M funding from Senator Barbara Mikulski.

“At that time, Denis and I anticipated that there would be new opportunities for physical scientists and engineers to collaborate with biomedical researchers and clinicians in solving problems in medicine, specifically problems at the molecular and nanoscale,” Searson said. “Since multidisciplinary collaborations across departments and divisions were not prevalent then, the deans of medicine, public health, engineering, and arts and sciences supported the creation of the institute to build the infrastructure to support and promote these efforts.” Then university president, William H. Brody arranged a meeting with Senator Barbara Mikulski, who officially launched the Institute on May 15, 2016.

Today INBT has more than 250 affiliated faculty members. INBT’s research occurs across all university campuses, but primarily in the 26,000 square feet of laboratory space for the 18 researchers located in Croft Hall on the University’s Homewood campus. Croft Hall serves as a focal point for INBT activities and headquarters for staff, where researchers from eight departments in the Whiting School of Engineering and the Johns Hopkins School of Medicine collaborate under one roof.

“INBT has catalyzed multidisciplinary research across the university,” said Landon King, executive vice dean of the Johns Hopkins School of Medicine. “The collaborations between engineers, scientists, and clinicians initiated by INBT have led to numerous discoveries, partnerships, and new companies.”

Since its launch, INBT researchers have generated more than $80 million in research funding. The institute manages a diverse portfolio of research projects and has established numerous research centers and initiatives, including the Physical Sciences-Oncology Center, Center for Cancer Nanotechnology Excellence, Center for Digital Pathology, and the Blood-Brain Barrier working group. INBT researchers have created more than 15 companies including Circulomics, Cancer Targeting Systems, Gemstone Biotherapeutics, Asclepyx, and LifeSprout.

INBT supports numerous education and training programs. An award from the Howard Hughes Medical Institute in 2006 provided the support for the development of the NanoBio training program. With funding from the National Institutes of Health and the National Science Foundation, 89 PhDs have been awarded to students from eight departments in the Whiting School of Engineering and the Krieger School of Arts and Sciences. INBT also supports a post-doctoral training program.

INBT is home to an NSF Research Experience for Undergraduates (REU) program, which has supported 104 students over eight years, and receives more than 700 applicants for 10 internships each year. All of these students have gone on to graduate studies in science and engineering. In addition, INBT hosts an International Research Experience for Students (IRES) program, providing internships for undergraduate and graduate students to work at IMEC, a world-class nano-fabrication facility in Leuven, Belgium.

In 2015, INBT launched an undergraduate research group as a way to build a community of students working in research labs. The more than 100 undergraduate student researchers are represented by the undergraduate leadership council, which organizes numerous professional development and social events to support and promote the research experience.

Story by Mary Spiro

Oxygen’s role in cancer spread

Cancer cells need oxygen to survive, as do most other life forms, but scientists had never tracked their search for oxygen in their early growth stages until now — a step toward a deeper understanding of one way cancer spreads that could help treat the disease.

In a paper published online by the Proceedings of the National Academy of Sciences, bioengineers from Johns Hopkins University and the University of Pennsylvania report results of their work showing how sarcoma cells in mice pursue a path toward greater concentrations of oxygen, almost as if they were following a widening trail of breadcrumbs. That path is suggested to lead the cells to blood vessels, through which the cells can spread to other parts of the body.

Oxygen-front.svg“If you think about therapeutic targets, you could target this process specifically,” said Sharon Gerecht, professor in Johns Hopkins University’s Whiting School of Engineering’s Department of Chemical and Biomolecular Engineering and a lead author of the study. She acknowledged that clinical application is a long way off, but said these results reached after three years of study in her laboratory provide clues about a key part of the life cycle of soft-tissue sarcomas and also a proven way to test cancer treatments in the lab. (Gerecht is an associate director of Johns Hopkins Institute for NanoBioTechnology.)

Sarcoma is a cancer that affects connective tissue, including bones, muscles, tendons, cartilage, nerves, fat and some blood vessels.  The study focused specifically on soft tissue sarcoma that does not affect bones, a type diagnosed in some 13,000 patients a year in the United States. Roughly a quarter to half of those patients develop recurring and spreading, or metastasizing, cancer.

Cancers of all sorts are known to thrive with little oxygen, and researchers have looked at the role of low oxygen conditions in tumor development. Less well understood is how cancer cells respond to varying oxygen concentrations in their early stages. That was the focus of this research.

Gerecht and her seven co-authors – four affiliated with Johns Hopkins, three with Penn – tracked thousands of early stage cancer cells taken from mice as they moved through a mockup of bodily tissue made of clear gel in a petri dish.  The hydrogel – a water-based material with the consistency of gelatin – replicates the environment surrounding cancer cells in human tissue.

Kyung Min Park, then a postdoctoral researcher in the Johns Hopkins lab, developed the hydrogel-cancer cell system, and Daniel Lewis, a Johns Hopkins graduate student, analyzed cellular migration and responses to rising oxygen concentrations, or “gradients.”

For this experiment, the hydrogels contained increasing concentrations of oxygen from the bottom of the hydrogel to the upper layer.  That allowed researchers to track how cancer cells respond to different levels of oxygen, both within a tumor and within body tissues.

Analysis of sarcoma tumors in mice, for instance, shows that the largest tumors have a large area of very low oxygen at the center. Smaller tumors have varying oxygen concentrations throughout.

The researchers’ first step was to show that cancer cells migrate more in low-oxygen or “hypoxic” hydrogels as compared with hydrogels containing as much oxygen as the surrounding atmosphere. They then looked at the direction of the cell movement.

In the hydrogel, which mimics the oxygen concentrations in smaller tumors, cells were found to move from areas of lower oxygen to higher. Researchers also found that the medication minoxidil – widely used to treat hair loss and known by its trade name Rogaine – stopped the movement of cancer cells through the hydrogel.

Cancer cells are known to modify their environment to make it easier for them to move through it, but this study takes that understanding a step further, Gerecht said.

“We did not know it was the oxygen” that effectively directs the movement, she said. “It’s suggesting oxygen gradient affects early stages of the metastasis process.”

The study also demonstrates the three-dimensional hydrogel model as an effective tool for testing cancer treatments in a laboratory, the authors wrote. Gerecht said a human patient’s cancer cells could be placed into the hydrogel just as the mouse cells were, allowing clinicians to see how they respond before treatments are given to patients.

The research was supported by the National Cancer Institute (grants CA153952 and CA158301), the American Heart Association (61675), the National Science Foundation (1054415) and Johns Hopkins University’s President’s Frontier Award.

Story by Arthur Hirsch: ahirsch6@jhu.edu