Bookmarks on Stem Cell Genes Preserve Cell Identity – Cornell Chronicle

Stem cells preserve their identities after cell division by using a series of protein bookmarks on their genes, according to new research published by scientists at Weill Cornell Medicine. The results may further the understanding of how certain diseases like cancer develop and could have broad clinical implications for preventing disease.

Pluripotent stem cells (PSCs) are cells that have the ability to transform into any kind of cell in the body. What type of cell each stem cell becomes called cell identity is determined by a tightly-controlled system regulated by various proteins. As these cells divide by mitosis, each so-called daughter cell produced should be the same type as its cell of origin. But during mitosis the control system is briefly disrupted, creating a window in which a cell can forget its identity and transform into a different kind of cell.

Dr. Effie Apostolou

If a cell doesnt remember what its supposed to be, it can transform into something else, even a malignant cell, saysDr. Effie Apostolou, an assistant professor of molecular biology in medicine and member of theSandra and Edward Meyer Cancer Centerat Weill Cornell Medicine. Understanding how this process is controlled is fundamental to understanding how many diseases arise.

In a paper published May 16 in Cell Reports, Dr. Apostolou and her team found that cell identity is preserved in pluripotent stem cells through a series of small modifications in proteins known as bookmarks on the cells genes. These bookmarks do not change during mitosis. So when the cell resumes its functions, such as transcription, after mitosis, this bookmark serves as a checkpoint to make sure that this process happens properly, Dr. Apostolou said. In this way, PSCs ensure that daughter cells are the same as their mother cells.

The researchers identified some proteins that were possible candidates for bookmarks and then removed those proteins from cells during the critical window in mitosis. If indeed this time window and the presence of these proteins are critical during mitosis, then the cell identity will be challenged, Dr. Apostolou said.

They found that when these mitotic bookmarks were degraded in PSCs, the cells were unable to maintain their identities: they did not reliably divide into the same kind of cell generation after generation. This tells us that these bookmarks are an important mechanism for keeping stem cells working properly, Dr. Apostolou said.

Because pluripotent stem cells hold great promise for prevention and treatment of many diseases, this finding is key, she said. Understanding cell identity is fundamental to understanding disease, as many, including cancer and some neurological diseases, are the result of cell identity being lost.

Mitosis can be either a crisis for cell identity or an opportunity for a new identity to arise she said. If we understand more about how cells maintain their identities during this process, we will better understand tumor formation and we may even be able to push stem cells into an identity that is therapeutically relevant for a given disease.

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Bookmarks on Stem Cell Genes Preserve Cell Identity - Cornell Chronicle

Single cell focus reveals hidden cancer cells – Medical Xpress

May 16, 2017 Single cell focus reveals hidden cancer cells. Credit: Shutterstock

Researchers have found a way to identify rogue cancer cells which survive treatment after the rest of the tumour is destroyed, by using a new technique that enables them to identify and characterise individual cancer cells.

Recent breakthroughs are revolutionising cancer treatment, enabling doctors to personalise chemotherapy for each patient. However, although these new treatments are often highly effective, all too often the cancer grows back, eventually causing relapse.

An international research team, led by Professors Adam Mead and Sten Eirik Jacobsen at the University of Oxford and Karolinska Institutet in Sweden, have found a way to identify rogue cancer cells which survive treatment after the rest of the tumour is destroyed, by using a new technique that enables them to identify and characterise individual cancer cells.

Professor Adam Mead of Oxford University's Radcliffe Department of Medicine, said: 'It is increasingly recognised that tumours contain a variety of different cell types, including so-called cancer stem cells, that drive the growth and relapse of a patient's cancer. These cells can be very rare and extremely difficult to find after treatment as they become hidden within the normal tissue.

'We used a new genetic technique to identify and analyse single cancer stem cells in leukaemia patients before and after treatment. We found that even in individual cases of leukaemia, there are various types of cancer stem cell that respond differently to the treatment. A small number of these cells are highly resistant to the treatment and are likely to be responsible for disease recurrence when the treatment is stopped. Our research allowed us uniquely to analyse these crucial cells that evade treatment so that we might learn how to more effectively eradicate them.

'This technique could be adapted to analyse a range of different cancers to help predict both the likely response to treatment, and the risk of the disease returning in the future. This should eventually enable treatment to be tailored to target each and every type of cancer stem cell that may be present.'

Molecularly targeted therapies for cancer frequently induce impressive remissions, however, complete disease elimination remains rare, and patients remain at risk of disease relapse. At a cellular level this is likely to reflect differences between individual cancer cells, so-called intratumoural heterogeneity, which underlies this differential response to treatment.

The researchers from the Weatherall Institute of Molecular Medicine at Oxford's Radcliffe Department of Medicine used a technique called single-cell analysis to study thousands of individual cancer cells in a type of blood cancer called chronic myeloid leukemia (CML) before and after treatment. Being able to identify each subpopulation using this single cell analysis technique will be an important step towards tailoring treatment to each patient.

Explore further: Proportion of cancer stem cells can increase over the course of cancer treatment

More information: Alice Giustacchini et al. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia, Nature Medicine (2017). DOI: 10.1038/nm.4336

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ReNeuron wins 1.8 million for cell therapy development – PharmaTimes

ReNeuron has won a 1.8 million grant from Innovate UK to advance its next generation commercial cell therapy manufacturing capabilities.

The award will support work being undertaken by the UK stem cell company and the Cell & Gene Therapy Catapult.

In particular it will fund key process development activities relating to up-scaled commercial manufacture of ReNeurons cell therapy candidates.

Sharon Grimster, general manager, Wales, at ReNeuron, said: We are delighted to have won this prestigious and highly competitive grant from Innovate UK. It enables us to further pursue and optimise our cell therapy manufacturing processes as our therapeutic programmes get closer to market.

The grant award will also assist ReNeuron in the execution of its strategy to ultimately bring the manufacture of its cell therapy candidates in-house to meet demand following market approval.

ReNeurons lead stem cell candidate is for patients left disabled by a stroke. Last year a Phase I trial of showed its CTX cell therapy candidate improved neurological function in patients with stable motor disability following a stroke for at least 24 months.

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ReNeuron wins 1.8 million for cell therapy development - PharmaTimes

Adoptive T-Cell Therapy Induced Response in Metastatic Uveal Melanoma – Cancer Network

More than one-third of patients with metastatic uveal melanoma had objective tumor regression when treated with adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs), according to results of an unplanned interim analysis published recently in Lancet Oncology.

We observed that a single infusion of TILs after a non-myeloablative lymphodepleting conditioning regimen could induce objective tumor regression, wrote Smita S. Chandran, PhD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland, and colleagues, including individuals whose disease was refractory to immune checkpoint blockade.

Unlike cutaneous melanoma, use of immune-based therapies in the rare uveal melanoma have been disappointing. Recent studies have shown that adoptive T-cell therapy led to salvage responses in a variety of refractory solid tumors. Therefore, with this study, Chandran and colleagues tested whether adoptive transfer of TILs could mediate tumor regression in uveal melanoma.

The phase II study included patients aged 16 or older with metastatic uveal melanoma. Metastasectomies were performed to obtain tumor tissue and generate the autologous TIL cultures. Patients were given lymphodepleting chemotherapy. The primary endpoint was objective tumor response.

The trial included 21 consecutive patients who received TIL therapy, of which 20 were evaluable. Of the 20 patients, seven (35%) had objective tumor regression.

These results challenge the belief that uveal melanoma is a cancer resistant to immunotherapy, wrote Chandran and colleagues.

One patient achieved a complete response of hepatic metastases. The additional six patients had partial responses, two of which are ongoing. Three of the responders were refractory to previous immune checkpoint blockage.

The precise mechanism for the anti-tumor responses observed in this study is still under investigation, the researchers wrote. All patients received a single cycle of fludarabine and cyclophosphamide, not intended as a direct cytotoxic therapy, but rather as a lymphocyte-depleting regimen before cell transfer to enhance T-cell engraftment and efficacy. Although neither of these chemotherapies has shown activity in metastatic melanoma, we cannot completely exclude their possible role in the tumor responses.

The most common grade 3 or worse chemotherapy-related adverse effects were lymphopenia, neutropenia, and thrombocytopenia.

In an editorial that accompanied the study, Kimberly M. Komatsubara, MD, and Richard D. Carvajal, MD, of Columbia University Medical Center in New York, wrote that the proportion of patients achieving a response as a measure of clinical efficacy is not an established surrogate for progression-free or overall survival in uveal melanoma and must be interpreted with caution. They added that further data will be important in interpreting the clinical effect of this therapy.

Although promising, the results reported by Chandran and colleagues are based on 20 assessable patients and thus must be considered preliminary, requiring confirmation in a larger patient population, they wrote. Overall, however, these data provide important evidence that the immune system can be harnessed to treat uveal melanoma and serves to identify adoptive transfer of TILs as a high-priority avenue of further research for patients with this disease

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Adoptive T-Cell Therapy Induced Response in Metastatic Uveal Melanoma - Cancer Network