And rationale for a potential new combined therapy to eradicate them
An international team of scientists, headed by researchers at UC San Diego School of Medicine and UC San Diego Moores Cancer Center, report that decreases in a specific group of proteins trigger changes in the cancer microenvironment that accelerate growth and development of therapy-resistant cancer stem cells (CSCs).
The discovery suggests the basis for a potential new therapeutic approach to eradicate blood cancers, which affect more than 1.1 million Americans. In fact, researchers found that in cell and mouse models, a treatment that employed a targeted monoclonal antibody effectively impaired the ability of CSCs to regenerate and made them easier to eradicate with existing enzyme-targeted (tyrosine kinase inhibitor) therapies.
The findings are published in the November 30 online issue of Proceedings of the National Academy of Sciences.
"This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival," said senior author Catriona Jamieson, MD, PhD, associate professor of medicine, chief of the Division of Regenerative Medicine and director of Stem Cell Research at Moores Cancer Center.
"Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia (CML) switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves," said Jamieson. "If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse - a leading cause of cancer-related mortality."
Jamieson and colleagues showed that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network - a mechanism that controls embryonic stem cell pluripotency and fate. One effect was reprogramming of progenitor cells into CSCs in blast crisis CML. Blast crisis occurs when there is 20 percent or more leukemia stem cells in the blood or bone marrow. It is the most advanced stage of leukemia.
The researchers found, however, that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted development of CSCs in their protected microenvironment, forcing them to enter the blood stream where dasatinib - a tyrosine kinase inhibitor - could effectively target them.
Co-authors include Frida Holm, Eva Hellqvist, Cayla N. Mason, Shawn A. Ali, Nathaniel Delos-Santos, Christian L. Barrett, Kelly A. Frazer and Anil Sadarangani, UC San Diego; Hye-Jung Chun, Richard A. Moore and Marco A. Marra, Canada's Michael Smith Genomes Sciences Centre; Mark D. Minden, Princess Margaret Hospital, Toronto; and Valerie Runza, Roche Pharmaceutical Research and Early Development, Germany.
Funding for this research came, in part, from the California Institute for Regenerative Medicine (DR1-01430), Leukemia Lymphoma Society Quest for Cures, Ratner Family Foundation, Sanford Stem Cell Clinical Center, Swedish Research Council and Swedish Childhood Cancer Foundation.
Full study: http://doi.
Scott LaFee | EurekAlert!
The secret sulfate code that lets the bad Tau in
16.07.2018 | American Society for Biochemistry and Molecular Biology
Colorectal cancer risk factors decrypted
16.07.2018 | Max-Planck-Institut für Stoffwechselforschung
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
16.07.2018 | Physics and Astronomy
16.07.2018 | Transportation and Logistics
16.07.2018 | Agricultural and Forestry Science