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Scientists use nanotechnology to detect bone-healing stem cells — ScienceDaily

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Researchers at the University of Southampton have developed a new way of using nanomaterials to identify and enrich skeletal stem cells — a discovery which could eventually lead to new treatments for major bone fractures and the repair of lost or damaged bone.

Working together, a team of physicists, chemists and tissue engineering experts used specially designed gold nanoparticles to ‘seek out’ specific human bone stem cells — creating a fluorescent glow to reveal their presence among other types of cells and allow them to be isolated or ‘enriched’.

The researchers concluded their new technique is simpler and quicker than other methods and up to 50-500 times more effective at enriching stem cells.

The study, led by Professor of Musculoskeletal Science, Richard Oreffo and Professor Antonios Kanaras of the Quantum, Light and Matter Group in the School of Physics and Astronomy, is published in ACS Nano — an internationally recognised multidisciplinary journal.

In laboratory tests, the researchers used gold nanoparticles — tiny spherical particles made up of thousands of gold atoms — coated with oligonucleotides (strands of DNA), to optically detect the specific messenger RNA (mRNA) signatures of skeletal stem cells in bone marrow. When detection takes place, the nanoparticles release a fluorescent dye, making the stem cells distinguishable from other surrounding cells, under microscopic observation. The stem cells can then be separated using a sophisticated fluorescence cell sorting process.

Stem cells are cells that are not yet specialised and can develop to perform different functions. Identifying skeletal stems cells allows scientists to grow these cells in defined conditions to enable the growth and formation of bone and cartilage tissue — for example, to help mend broken bones.

Among the challenges posed by our ageing population is the need for novel and cost-effective approaches to bone repair. With one in three women and one in five men at risk of osteoporotic fractures worldwide, the costs are significant, with bone fractures alone costing the European economy €17 billion and the US economy $20 billion annually.

Within the University of Southampton’s Bone and Joint Research Group, Professor Richard Oreffo and his team have been looking at bone stem cell based therapies for over 15 years to understand bone tissue development and to generate bone and cartilage. Over the same time-period, Professor Antonios Kanaras and his colleagues in the Quantum, Light and Matter Group have been designing novel nanomaterials and studying their applications in the fields of biomedical sciences and energy. This latest study effectively brings these disciplines together and is an exemplar of the impact collaborative, interdisciplinary working can bring.

Professor Oreffo said: “Skeletal stem cell based therapies offer some of the most exciting and promising areas for bone disease treatment and bone regenerative medicine for an aging population. The current studies have harnessed unique DNA sequences from targets we believe would enrich the skeletal stem cell and, using Fluorescence Activated Cell Sorting (FACS) we have been able to enrich bone stem cells from patients. Identification of unique markers is the holy grail in bone stem cell biology and, while we still have some way to go; these studies offer a step change in our ability to target and identify human bone stem cells and the exciting therapeutic potential therein.”

Professor Oreffo added: “Importantly, these studies show the advantages of interdisciplinary research to address a challenging problem with state of the art molecular/cell biology combined with nanomaterials’ chemistry platform technologies.”

Professor Kanaras said: “The appropriate design of materials is essential for their application in complex systems. Customizing the chemistry of nanoparticles we are able to program specific functions in their design.

“In this research project, we designed nanoparticles coated with short sequences of DNA, which are able to sense HSPA8 mRNA and Runx2 mRNA in skeletal stem cells and together with advanced FACS gating strategies, to enable the assortment of the relevant cells from human bone marrow.

“An important aspect of the nanomaterial design involves strategies to regulate the density of oligonucleotides on the surface of the nanoparticles, which help to avoid DNA enzymatic degradation in cells. Fluorescent reporters on the oligonucleotides enable us to observe the status of the nanoparticles at different stages of the experiment, ensuring the quality of the endocellular sensor.”

Both lead researchers also recognise that the accomplishments were possible due to the work of all the experienced research fellows and PhD students involved in this research as well as collaboration with Professor Tom Brown and Dr Afaf E-Sagheer of the University of Oxford, who synthesised a large variety of functional oligonucleotides.

The scientists are currently applying single cell RNA sequencing to the platform technology developed with partners in Oxford and the Institute for Life Sciences (IfLS) at Southampton to further refine and enrich bone stem cells and assess functionality. The team propose to then move to clinical application with preclinical bone formation studies to generate proof of concept studies.

The work has been possible through a BBSRC project grant to Professor Oreffo and Professor Kanaras.

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Opening the door for hematopoiesis research — ScienceDaily

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Most people have heard of stem cells, cells from which all other cells with specialized functions are generated. Hematopoietic stem cells (HSCs) are the architects of blood cell development and are responsible for blood cell formation throughout the life of an organism. HSCs are also used in the treatment of cancer and immune disturbances.

Previous research into HSC transplantation has involved the use of adult and fetal mice. This has involved the removal of recipient HSCs using approaches including irradiation and the administration of DNA damaging drugs. In a first of its kind, researchers from the University of Tsukuba devised a novel approach for HSC deletion in mouse embryos. This report provides the first description of embryonic HSC depletion and transplantation of donor HSCs into the embryo via the placenta.

In describing their approach, Assistant Professor Michito Hamada says: “We were able to exploit the genetics of HSC development in mice to generate mice that completely lack HSCs in the fetal liver, making these mice the perfect recipients for HSC transplantation.” Mice lacking the Runx1 gene do not survive into adulthood and die at embryonic day 12.5, in part because they lack HSCs. The recipient mice developed by this team have Runx1 transgenes that partially restore the effects of Runx1 absence, and while these mice still lack HSCs, they can develop until embryonic day 18.5.

Using these recipient mice, the research team explored the effects of transplanting HSCs from the same species (allogenic) or from a different species (xenogeneic). The placentas of recipient mice were injected with donor HSCs at embryonic day 11.5, before the development of the immune system. Excitingly, over 90% the HSCs of recipient fetuses were from the donor, irrespective of species.

Analysis of the HSCs that developed in recipient mice after transportation revealed that they contributed to the development of both white and red blood cells. Furthermore, additional transplant of these cells into adult recipients revealed that the HSCs were functional and had retained normal abilities.

“These results are really exciting,” explains Professor Satoru Takahashi. “These mice represent a new tool that can be used to advance HSC research. The ability to perform HSC transplants at an earlier developmental stage really allows us to explore fetal hematopoiesis and, in the future, this model could be ‘humanized’ using human HSCs. The applications appear endless.”

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The advance could lead to the development of stem cell-based therapies for muscle loss or damage due to injury, age or disease — ScienceDaily

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A UCLA-led research team has identified a chemical cocktail that enables the production of large numbers of muscle stem cells, which can self-renew and give rise to all types of skeletal muscle cells.

The advance could lead to the development of stem cell-based therapies for muscle loss or damage due to injury, age or disease. The research was published in Nature Biomedical Engineering.

Muscle stem cells are responsible for muscle growth, repair and regeneration following injury throughout a person’s life. In fully grown adults, muscle stem cells are quiescent — they remain inactive until they are called to respond to injury by self-replicating and creating all of the cell types necessary to repair damaged tissue.

But that regenerative capacity decreases as people age; it also can be compromised by traumatic injuries and by genetic diseases such as Duchenne muscular dystrophy.

“Muscle stem cell-based therapies show a lot of promise for improving muscle regeneration, but current methods for generating patient-specific muscle stem cells can take months,” said Song Li, the study’s senior author and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Li and his colleagues identified a chemical cocktail — a combination of the root extract forskolin and the small molecule RepSox — that can efficiently create large numbers of muscle stem cells within 10 days. In mouse studies, the researchers demonstrated two potential avenues by which the cocktail could be used as a therapy.

The first method uses cells found in the skin called dermal myogenic cells, which have the capacity to become muscle cells. The team discovered that treating dermal myogenic cells with the chemical cocktail drove them to produce large numbers of muscle stem cells, which could then be transplanted into injured tissue.

Li’s team tested that approach in three groups of mice with muscle injuries: adult (8-week-old) mice, elderly (18-month-old) mice and adult mice with a genetic mutation similar to the one that causes Duchenne in humans.

Four weeks after the cells were transplanted, the muscle stem cells had integrated into the damaged muscle and significantly improved muscle function in all three groups of mice.

For the second method, Li’s team used nanoparticles to deliver the chemical cocktail into damaged muscle tissue. The nanoparticles, which are about one one-hundredth the size of a grain of sand, are made of the same material as dissolvable surgical stitches, and they are designed to release the chemicals slowly as they break down.

The second approach also produced a robust repair response in all three types of mice. When injected into injured muscle, the nanoparticles migrated throughout the injured area and released the chemicals, which activated the quiescent muscle stem cells to begin dividing.

While both techniques were successful, the key benefit of the second one is that it eliminated the need for growing cells in the lab — all of the muscle stem cell activation and regeneration takes place inside the body.

The team was particularly surprised to find that the second method was effective even in elderly mice, in spite of the fact that as animals age, the environment that surrounds and supports muscle stem cells becomes less effective.

“Our chemical cocktail enabled muscle stem cells in elderly mice to overcome their adverse environment and launch a robust repair response,” said Li, who is also chair of bioengineering at the UCLA Samueli School of Engineering and professor of medicine at the David Geffen School of Medicine at UCLA.

In future studies, the research team will attempt to replicate the results in human cells and monitor the effects of the therapy in animals for a longer period. The experiments should help determine if either approach could be used as a one-time treatment for patients with serious injuries.

Li noted that neither approach would fix the genetic defect that causes Duchenne or other genetic muscular dystrophies. However, the team envisions that muscle stem cells generated from a healthy donor’s skin cells could be transplanted into a muscular dystrophy patient’s muscle — such as in the lungs — which could extend their lifespan and improve their quality of life.

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New bioink brings 3D-printing of human organs closer to reality — ScienceDaily

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Researchers at Lund University in Sweden have designed a new bioink which allows small human-sized airways to be 3D-bioprinted with the help of patient cells for the first time. The 3D-printed constructs are biocompatible and support new blood vessel growth into the transplanted material. This is an important first step towards 3D-printing organs. The new study has been published in Advanced Materials.

Chronic lung diseases are the third leading cause of death worldwide with an EU cost of more than €380 billion annually. For many chronic diseases there is no cure and the only end-stage option for patients is lung transplantation. However, there are not enough donor lungs to meet clinical demand.

Therefore, researchers are looking at ways to increase the amount of lungs available for transplantation. One approach is fabricating lungs in the lab by combining cells with a bioengineered scaffold.

“We started small by fabricating small tubes, because this is a feature found in both airways and in the vasculature of the lung. By using our new bioink with stem cells isolated from patient airways, we were able to bioprint small airways which had multiple layers of cells and remained open over time,” explains Darcy Wagner, Associate Professor and senior author of the study.

The researchers first designed a new bioink (a printable material with cells) for 3D-bioprinting human tissue. The bioink was made by combining two materials: a material derived from seaweed, alginate, and extracellular matrix derived from lung tissue.

This new bioink supports the bioprinted material over several stages of its development towards tissue. They then used the bioink to 3D-bioprint small human airways containing two types of cells found in human airways. However, this bioink can be adapted for any tissue or organ type.

“These next generation bioinks also support the maturation of the airway stem cells into multiple cell types found in adult human airways, which means that less cell types need to be printed, simplifying the nozzle numbers needed to print tissue made of multiple cell types,” says Darcy Wagner.

Wagner notes that the resolution needs to be improved to 3D-bioprint more distal lung tissue and the air sacks, known as alveoli, that are vital for gas exchange.

“We hope that further technological improvements of available 3D printers and further bioink advances will allow for bioprinting at a higher resolution in order to engineer larger tissues which could be used for transplantation in the future. We still have a long way to go,” she says.

The team used a mouse model closely resembling the immunosuppression used in patients undergoing organ transplantation. When transplanted, they found that 3D-printed constructs made from the new bioink were well-tolerated and supported new blood vessels.

“The development of this new bioink is a significant step forward, but it is important to further validate the functionality of the small airways over time and to explore the feasibility of this approach in large animal models,” concludes Martina De Santis, the first author of the study.

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Cellular benefits of gene therapy seen decades after treatment — ScienceDaily

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An international collaboration between Great Ormond Street Hospital, the UCL GOS Institute for Child Health and Harvard Medical School has shown that the beneficial effects of gene therapy can be seen decades after the transplanted blood stem cells has been cleared by the body.

The research team monitored five patients who were successfully cured of SCID-X1 using gene therapy at GOSH. For 3-18 years patients’ blood was regularly analysed to detect which cell types and biomarker chemicals were present in their blood. The results showed that even though the stem cells transplanted as part of gene therapy had been cleared by the patients, the all-important corrected immune cells, called T-cells, were still forming.

Gene therapy works by first removing some of the patients’ blood-forming stem cells, which create all types of blood and immune cells. Next, a viral vector is used to deliver a new copy of the faulty gene into the DNA of the patients’ cells in a laboratory. These corrected stem cells are then returned to patients in a so-called ‘autologous transplant’, where they go on to produce a continual supply of healthy immune cells capable of fighting infection.

In the gene therapy for SCID-X1 the corrected stem cells have been eventually cleared by the body but the patients remained cured of their condition. This team of researchers suggested that the ‘cure’ was down to the fact that the body was still able to continually produce newly-engineered T cells — an important part of the body’s immune system.

They used state-of-the-art gene tracking technology and numerous tests to give unprecedented details of the T cells in SCID-X1 patients decades after gene therapy.

The team believe that this gene therapy has created the ideal conditions for the human thymus (the part of the body where T cells develop) to host a long-term store of the correct type of progenitor cells that can form new T cells. Further investigation of how this happens and how it can be exploited could be crucial for the development of next generation gene therapy and cancer immunotherapy approaches.

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Altered cell divisions cause hair thinning — ScienceDaily

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Hair grows from stem cells residing in hair follicles. During aging, the capability of hair follicles to grow hair is successively lost, leading to hair thinning and ultimately hair loss. In a new study, researchers from Tokyo Medical and Dental University (TMDU) and the University of Tokyo identified a novel mechanism by which hair follicles lose their regenerative capabilities.

Hair follicles are mini-organs from which new hair constantly grows. The basis for new hair growth is the proper function of hair follicle stem cells (HFSCs). HFSCs undergo cyclic symmetric and asymmetric cell divisions (SCDs and ACDs). SCDs generate two identical cells that go on to have the same fate, while ACDs generate a differentiating cell and a self-renewing stem cell. The combination ensures that the stem cell population continues to exist, yet how those contribute to the loss of HFSC function due to aging is not yet completely understood.

“For proper tissue function, symmetric and asymmetric cell divisions have to be in balance,” says corresponding author of the study Emi Nishimura. “Once stem cells preferentially undergo one of either or, worse yet, deviate from the typical process of either type of cell division, the organ suffers. In this study, we wanted to understand how stem cell division plays into hair grows during aging.”

To achieve their goal, the researchers investigated stem cell division in HFSCs in young and aged mice by employing two different types of assays: Cell fate tracing and cell division axis analyses. In the former, HFSCs were marked with a fluorescent protein so they could be followed over time, while in the latter the angle of HFSC division was measured. Strikingly, the researchers were able to show that while HFSCs in young mice underwent typical symmetric and asymmetric cell divisions to regenerate hair follicles, during aging they adopted an atypical senescent type of asymmetric cell division.

But why does the mode of cell division change so drastically during aging? To answer this question, the researchers focused on hemidesmosomes, a class of protein that connect the cells to the extracellular matrix (ECM; proteins surrounding cells). Cell-ECM have long been known to confer polarity to cells, i.e., that the cells can sense their localization within a given space through the action of specific proteins. The researchers found that during aging both hemidesmosomal and cell polarity proteins become destabilized, resulting in the generation of aberrantly differentiating cells during division of HFSCs. As a result, HFSCs become exhausted and lost (leading to hair thinning and hair loss) over time.

“These are striking results that show how hair follicles lose their ability to regenerate hair over time,” says first author of the study Hiroyuki Matsumura. “Our results may contribute to the development of new approaches to regulate organ aging and aging-associated diseases.”

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How to speed up muscle repair — ScienceDaily

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A study led by researchers at the University of California San Diego Jacobs School of Engineering provides new insights for developing therapies for muscle disease, injury and atrophy. By studying how different pluripotent stem cell lines build muscle, researchers have for the first time discovered how epigenetic mechanisms can be triggered to accelerate muscle cell growth at different stages of stem cell differentiation.

The findings were published Mar. 17 in Science Advances.

“Stem cell-based approaches that have the potential to aid muscle regeneration and growth would improve the quality of life for many people, from children who are born with congenital muscle disease to people who are losing muscle mass and strength due to aging,” said Shankar Subramaniam, distinguished professor of bioengineering, computer science and engineering, and cellular and molecular medicine at UC San Diego and lead corresponding author on the study. “Here, we have discovered that specific factors and mechanisms can be triggered by external means to favor rapid growth.”

The researchers used three different human induced pluripotent stem cell lines and studied how they differentiate into muscle cells. Out of the three, one cell line grew into muscle the fastest. The researchers looked at what factors made this line different from the rest, and then induced these factors in the other lines to see if they could accelerate muscle growth.

They found that triggering several epigenetic mechanisms at different time points sped up muscle growth in the “slower” pluripotent stem cell lines. These include inhibiting a gene called ZIC3 at the outset of differentiation, followed by adding proteins called beta-catenin transcriptional cofactors later on in the growth process.

“A key takeaway here is that all pluripotent stem cells do not have the same capacity to regenerate,” Subramaniam said. “Identifying factors that will prime these cells for specific regeneration will go a long way in regenerative medicine.”

Next, the team will explore therapeutic intervention, such as drugs, that can stimulate and accelerate muscle growth at different stages of differentiation in human induced pluripotent stem cells. They will also see whether implanting specific pluripotent stem cells in dystrophic muscle can stimulate new muscle growth in animals. Ultimately, they would like to see if such a stem cell-based approach could regenerate muscle in aging humans.

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Materials provided by University of California – San Diego. Original written by Liezel Labios. Note: Content may be edited for style and length.

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Double trouble for drug-resistant cancers — ScienceDaily

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ETC-159, a made-in-Singapore anti-cancer drug that is currently in early phase clinical trials for use in a subset of colorectal and gynaecological cancers, could also prevent some tumours from resisting therapies by blocking a key DNA repair mechanism, researchers from Duke-NUS Medical School and the Agency for Science, Technology and Research (A*STAR) in Singapore reported in the journal EMBO Molecular Medicine.

Among the many therapies used to treat cancers, inhibitors of the enzyme poly (ADP ribose) polymerase (PARP) prevent cancer cells from repairing naturally occurring DNA damage, including unwanted/harmful breaks in the DNA. When too many breaks accumulate, the cell dies.

“Some cancers have an overactive Wnt signalling pathway that may make them resistant to this sort of DNA damage,” said Assistant Professor Babita Madan, from Duke-NUS’ Cancer and Stem Cell Biology (CSCB) Programme and a senior author of the study. “Understanding how this pathway drives resistance to existing therapies could lead to the development of novel anti-cancer treatments.”

Normally, Wnt signalling proteins interact with cell receptors to activate the translocation of another protein, called beta-catenin, into the nucleus, where it regulates the activation of several genes.

“We found that, when Wnt signalling sends beta-catenin into the nucleus, it activates a family of DNA break repair genes,” said Professor David Virshup, director of the CSCB Programme and co-senior author of the study. “Cancers with excessive Wnt signalling, like colorectal cancer, therefore, have an enhanced ability to repair DNA breaks and thus escape the effects of PARP inhibitors.”

The team found that blocking Wnt signalling with a drug called ETC-159 reversed PARP inhibitor resistance in several cancer cell lines.

ETC-159 inhibits an enzyme called porcupine, which in turn, prevent the secretion of Wnt proteins. ETC-159 is being tested in a clinical trial for use in cancers with overactive Wnt signalling, amongst other therapeutic indications

Analysis of this pre-clinical study shows that therapeutic doses of ETC-159 appear to be well tolerated by the gut, without causing toxicity. This means that a low dose of ETC-159, when given alongside PARP inhibitors, could prevent cancer resistance to treatment with PARP inhibitors while sparing intestinal stem cells, providing further options for treating cancers with hyperactive Wnt signalling.

Through this study, the researchers also learned that the same signal for DNA repair helps to prevent mutations from developing in stem cells residing inside the intestinal epithelium, further confirming the importance of normal Wnt signalling in stem cell maintenance.

ETC-159 was jointly developed by Duke-NUS and the Experimental Drug Development Centre (EDDC), a national platform for drug discovery and development hosted by A*STAR. The Wnt-pathway inhibitor is a novel small-molecule drug candidate that targets a range of cancers. It is currently progressing through clinical trials as a treatment for a subset of colorectal and gynaecological cancers.

“These findings improve our understanding of how Wnt signalling enhances DNA repair in stem cells and cancers, maintaining their genomic integrity,” said Dr May Ann Lee, a group head at EDDC and also a senior author of the study. “Conversely, interventions that block Wnt signalling could cause some cancers to be more sensitive to radiation and other DNA damaging agents.”

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Treatment for type-2 diabetic heart disease — ScienceDaily

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University of Otago researchers have discovered one of the reasons why more than 50 per cent of people with type 2 diabetes die from heart disease.

And perhaps more significantly, they have found how to treat it.

Associate Professor Rajesh Katare, of the Department of Physiology, says it has been known that stem cells in the heart of diabetic patients are impaired. While stem cell therapy has proved effective in treating heart disease, it is not the case in diabetic hearts.

It has not been known why; until now.

It comes down to tiny molecules called microRNA which control gene expression.

“Based on the results of laboratory testing, we identified the number of microRNAs that are impaired in stem cells of the diabetic heart,” Associate Professor Katare says.

“Among several microRNAs we identified that one particular microRNA called miR-30c — which is crucial for the stem cells’ survival, growth and new blood vessel formation — is reduced in the diabetic stem cells. All these functions are required for stem cell therapy to be successful in the heart.

“Importantly, we also confirmed that this microRNA is decreased in the stem cells collected from the heart tissue of the patients undergoing heart surgery at Dunedin Hospital.”

Researchers were able to then increase the level of the lacking miR-30c in the heart by a “simple injection.”

“This resulted in significantly improving the survival and growth of stem cells in the diabetic heart,” Associate Professor Katare says.

“This fascinating discovery has newly identified that impairment in the microRNAs is the underlying reason for the stem cells being not functional in the diabetic heart. More importantly, the results have identified a novel therapy for activation of stem cells in the heart using microRNA, without the need to inject stem cells, which is a time and cost consuming process.”

Associate Professor Katare calls the finding “significant” and says it could help diabetes- sufferers — who are ten per cent of New Zealanders — lead a longer, quality life.

“Apart from identifying the reasons for poor stem cells function in a patient with diabetes, the novel therapy of using microRNA could change the treatment method for heart disease in diabetic individuals.”

Researchers will now undertake more laboratory testing before moving on to humans.

“Our initial analysis revealed that there might be another four potential candidate microRNAs. Therefore, it is essential to test the function of those microRNAs as well. It may be possible that combination therapy with more than one microRNA could further increase the beneficial effects.”

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Retracing the history of the mutation that gave rise to cancer decades later — ScienceDaily

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There is no stronger risk factor for cancer than age. At the time of diagnosis, the median age of patients across all cancers is 66. That moment, however, is the culmination of years of clandestine tumor growth, and the answer to an important question has thus far remained elusive: When does a cancer first arise?

At least in some cases, the original cancer-causing mutation could have appeared as long as 40 years ago, according to a new study by researchers at Harvard Medical School and the Dana-Farber Cancer Institute.

Reconstructing the lineage history of cancer cells in two individuals with a rare blood cancer, the team calculated when the genetic mutation that gave rise to the disease first appeared. In a 63-year-old patient, it occurred at around age 19; in a 34-year-old patient, at around age 9.

The findings, published in the March 4 issue of Cell Stem Cell, add to a growing body of evidence that cancers slowly develop over long periods of time before manifesting as a distinct disease. The results also present insights that could inform new approaches for early detection, prevention, or intervention.

“For both of these patients, it was almost like they had a childhood disease that just took decades and decades to manifest, which was extremely surprising,” said co-corresponding study author Sahand Hormoz, HMS assistant professor of systems biology at Dana-Farber.

“I think our study compels us to ask, when does cancer begin, and when does being healthy stop?” Hormoz said. “It increasingly appears that it’s a continuum with no clear boundary, which then raises another question: When should we be looking for cancer?”

In their study, Hormoz and colleagues focused on myeloproliferative neoplasms (MPNs), a rare type of blood cancer involving the aberrant overproduction of blood cells. The majority of MPNs are linked to a specific mutation in the gene JAK2. When the mutation occurs in bone marrow stem cells, the body’s blood cell production factories, it can erroneously activate JAK2 and trigger overproduction.

To pinpoint the origins of an individual’s cancer, the team collected bone marrow stem cells from two patients with MPN driven by the JAK2 mutation. The researchers isolated a number of stem cells that contained the mutation, as well normal stem cells, from each patient, and then sequenced the entire genome of each individual cell.

Over time and by chance, the genomes of cells randomly acquire so-called somatic mutations — nonheritable, spontaneous changes that are largely harmless. Two cells that recently divided from the same mother cell will have very similar somatic mutation fingerprints. But two distantly related cells that shared a common ancestor many generations ago will have fewer mutations in common because they had the time to accumulate mutations separately.

Cell of origin

Analyzing these fingerprints, Hormoz and colleagues created a phylogenetic tree, which maps the relationships and common ancestors between cells, for the patients’ stem cells — a process similar to studies of the relationships between chimpanzees and humans, for example.

“We can reconstruct the evolutionary history of these cancer cells, going back to that cell of origin, the common ancestor in which the first mutation occurred,” Hormoz said.

Combined with calculations of the rate at which mutations accumulate, the team could estimate when the JAK2 mutation first occurred. In the patient who was first diagnosed with MPN at age 63, the team found that the mutation arose around 44 years prior, at the age of 19. In the patient diagnosed at age 34, it arose at age 9.

By looking at the relationships between cells, the researchers could also estimate the number of cells that carried the mutation over time, allowing them to reconstruct the history of disease progression.

“Initially, there’s one cell that has the mutation. And for the next 10 years there’s only something like 100 cancer cells,” Hormoz said. “But over time, the number grows exponentially and becomes thousands and thousands. We’ve had the notion that cancer takes a very long time to become an overt disease, but no one has shown this so explicitly until now.”

The team found that the JAK2 mutation conferred a certain fitness advantage that helped cancerous cells outcompete normal bone marrow stem cells over long periods of time. The magnitude of this selective advantage is one possible explanation for some individuals’ faster disease progression, such as the patient who was diagnosed with MPN at age 34.

In additional experiments, the team carried out single-cell gene expression analyses in thousands of bone marrow stem cells from seven different MPN patients. These analyses revealed that the JAK2 mutation can push stem cells to preferentially produce certain blood cell types, insights that may help scientists better understand the differences between various MPN types.

Together, the results of the study offer insights that could motivate new diagnostics, such as technologies to identify the presence of rare cancer-causing mutations currently difficult to detect, according to the authors.

“To me, the most exciting thing is thinking about at what point can we detect these cancers,” Hormoz said. “If patients are walking into the clinic 40 years after their mutation first developed, could we have caught it earlier? And could we prevent the development of cancer before a patient ever knows they have it, which would be the ultimate dream?”

The researchers are now further refining their approach to studying the history of cancers, with the aim of helping clinical decision-making in the future.

While their approach is generalizable to other types of cancer, Hormoz notes that MPN is driven by a single mutation in a very slow growing type of stem cell. Other cancers may be driven by multiple mutations, or in faster-growing cell types, and further studies are needed to better understand the differences in evolutionary history between cancers.

The team’s current efforts include developing early detection technologies, reconstructing the histories of greater numbers of cancer cells, and investigating why some patients’ mutations never progress into full-blown cancer, but others do.

“Even if we can detect cancer-causing mutations early, the challenge is to predict which patients are at risk of developing the disease, and which are not,” Hormoz said. “Looking into the past can tell us something about the future, and I think historical analyses such as the ones we conducted can give us new insights into how we could be diagnosing and intervening.”

Study collaborators include scientists and physicians from Brigham and Women’s Hospital, Boston Children’s Hospital, Massachusetts General Hospital, and the European Bioinformatics Institute. The other co-corresponding authors of the study are Ann Mullally and Isidro Cortés-Ciriano.

The study was supported in part by the National Institutes of Health (grants R00GM118910, R01HL158269), the Jayne Koskinas Ted Giovanis Foundation for Health and Policy, the William F. Milton Fund at Harvard University, an AACR-MPM Oncology Charitable Foundation Transformative Cancer Research grant, Gabrielle’s Angel Foundation for Cancer Research, and the Claudia Adams Barr Program in Cancer Research.

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