Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Discovery of an embryonic switch for cancer stem cell generation

01.12.2015

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).


An oversized bone marrow cell, typical of chronic myeloid leukemia, is shown.

Credit: Difu Wu

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.org/10.1073/pnas.1506943112

Media Contact

Scott LaFee
slafee@ucsd.edu
619-543-6163

 @UCSanDiego

http://www.ucsd.edu 

Scott LaFee | EurekAlert!

More articles from Life Sciences:

nachricht A novel socio-ecological approach helps identifying suitable wolf habitats
17.02.2017 | Universität Zürich

nachricht New, ultra-flexible probes form reliable, scar-free integration with the brain
16.02.2017 | University of Texas at Austin

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Switched-on DNA

20.02.2017 | Materials Sciences

Second cause of hidden hearing loss identified

20.02.2017 | Health and Medicine

Prospect for more effective treatment of nerve pain

20.02.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>