November 30, 2020
Researchers find 3-D structure of the genome is behind the self-renewing capabilities of blood stem cells
OICR-funded researchers open a new path to discover drivers of chemotherapy resistance and cancer relapse
Stem cells have the capability to self-renew and create other types of cells, but not all stem cells are equal. OICR-supported researchers at the Princess Margaret Cancer Centre, Drs. Mathieu Lupien and John Dick, have discovered a new way to distinguish the self-renewing capabilities of stem cells, revealing new ways to study the origins of cancer and cancer recurrence.
In their recently published study in Cell Stem Cell, Lupien, Dick and collaborators identified how some blood – or hematopoetic – stem cells can self-renew but others lose that ability. They found differences in the three-dimensional structure of the genetic information between different stem cell types.
DNA within each human cell, including stem cells, is coiled and compacted in a highly regulated way into structures called chromatin. Depending on how DNA is compacted into chromatin, some regions of DNA are accessible to gene-expressing cellular machinery while some aren’t, influencing how genes are expressed and how a cell may behave. The study group identified that this chromatin accessibility is a key component of a cell’s self-renewing capabilities and “stemness”.
“Enabled by the latest technologies, we found that the pattern of closed – or inaccessible – regions of DNA and the open or accessible regions differ between the long-term self-renewing stem cells and other more mature blood cell populations” says Lupien, Senior Scientist at the Princess Margaret Cancer Centre, Associate Professor at the University of Toronto and OICR Investigator.
The study discovered that the self-renewal capabilities are specifically linked to parts of the genome that bind a protein that is responsible for chromatin folding, called CTCF. As cancer researchers, Lupien and Dick are now applying these discoveries made in normal stem cells to study cancer stem cells. It is thought that if a cancer treatment cannot eliminate the cancer’s stem cells, these surviving self-renewing cells can give rise to recurrent tumours. With a better understanding of cancer stem cells, researchers can investigate the roots of cancer and how to potentially target or manipulate the mechanisms behind self-renewal.
This breakthrough study was made possible by Lupien’s expertise in epigenetics, the field that studies gene expression, Dick’s expertise in stemness and blood development, and the contributions of collaborators and trainees, including Drs. Naoya Takayama and Alex Murison who led the wet lab assays and bioinformatics analyses respectively.
“Understanding how stemness is controlled is key to being able to harness the power of stem cells for cell-based therapies, but also to understand how malignant cells perturb stemness to allow the cancer stem cells to continue to propagate tumor growth,” says Dick, Senior Scientist at the Princess Margaret Cancer Centre, Professor at the University of Toronto and lead of OICR’s Acute Leukemia Translational Research Initiative. “We look forward to furthering our understanding of hematopoiesis and bringing these insights closer to clinical application.”
September 30, 2019
McMaster University researcher and OICR Investigator, Dr. Kristin Hope, turns her stem cell discovery into a new treatment approach for leukemia.
A few years ago, Dr. Kristin Hope and her research team discovered a new way to grow rare life-saving blood stem cells. Now, the Hope Lab is using this discovery to suppress leukemic stem cells – the cells at the “root” of leukemia.
In their most recent study, published earlier this month in Cancer Research, the Hope Lab discovered that the same molecular pathway they found previously could be turned off to grow healthy stem cells could be turned on to impair the development of cancer stem cells.
The study suggests that this pathway, called the aryl hydrocarbon receptor (AHR) signaling pathway, could be leveraged as a potential therapeutic approach for acute myeloid leukemia – one of the most common subtypes of leukemia.
“We saw a loss of leukemic stem cells by activating – or turning on – the AHR pathway,” Hope says. “This brings us a step closer to a potential new therapy for patients with leukemia.”
The study group used a small molecule to activate the AHR pathway, finding that it had a significant effect in eliminating leukemic stem cells, but no effect on healthy cells. The group found similar results in cell cultures as well as in mice that were transplanted with human leukemia cells.
Hope, who is a Principal Investigator at McMaster University’s Stem Cell and Cancer Research Institute, will continue investigating this small molecule as a potential drug that could complement chemotherapies in the future.
“We will continue building on our understanding of the AHR pathway and how to control it,” she says. “This understanding will help us in the development of new therapies so that our discoveries can one day help patients.”
October 24, 2017
Brain tumours resulting from the spread of cancer from its primary location, known as brain metastases (BM), are the most common form of brain tumours in adults. A team of Ontario-based researchers recently identified two genes that seem to play a central role in BM in lung cancer patients – findings that could lead to improved biomarkers and treatments for BM.
In a study published in the journal Acta Neuropatologica, Mohini Singh and her collaborators focused on a class of cells they have termed Brain Metastases Initiating Cells (BMICs), which leave the primary site of cancer and migrate to the brain.
Singh, a biochemistry PhD candidate in the lab of Dr. Sheila Singh at McMaster University, explains the approach the team took to study these cells. “There was a lack of preclinical models that we could use to comprehensively study BMICs and understand the mechanisms behind them. To conduct our study we used brain metastases from lung cancer patients, which we cultured in conditions to enrich for BMICs, and then transplanted them into mice. This method allowed us to study BMICs within a living host, which provides a more accurate representation of the development of brain metastasis in humans.”
The researchers performed in vitro and in vivo RNA interference screens utilizing their unique BM models, and found two genes that were essential to the regulation of BMICs: SPOCK1 and TWIST2. “We discovered that SPOCK1 is a regulator of self-renewal in BMICs, playing a role in the initiation of lung tumours and their metastasis to the brain,” explains Singh. Furthermore, the results were clinically relevant. “Increased SPOCK1 expression was seen in lung cancer biopsies of patients with known brain metastases, and was correlated with poor survival.” Through protein-protein interaction mapping the researchers also identified new pathway interactors of the two genes that could be used as novel targets in treatment of BM in lung cancer patients.
“Identifying these two genes could be of great use in improving the treatment of lung cancer. In the future we could predict those patients who are most at risk of developing a brain metastasis and use drugs to target BMIC regulatory genes such as SPOCK1 and TWIST2 to destroy the initiating cells and to block the spread,” says Singh. “This would result in keeping the lung cancer locally controlled and therefore more treatable.”
OICR funding was used to establish this study with further significant funding coming from the Canadian Cancer Society and the Brain Canada Studentship.
August 17, 2017
Research from McMaster University has identified new regulators of brain metastases in patients with lung cancer.
These regulators are the genes called SPOCK1 and TWIST2.
July 11, 2017
The rising use of stem cell-based therapies has illustrated the power of stem cells to treat a number of diseases. Now a group of Ontario researchers are looking at the promise of stem cells from a different perspective. Amongst other efforts, they are developing and testing new therapies that target and kill leukemic stem cells to lessen the chances of acute leukemias (AL) coming back following standard treatment.
June 28, 2017
By combining new knowledge from the fields of stem cell biology and genetics, a group of Ontario researchers led by Dr. John Dick have solved the mystery of why some acute myeloid leukemia (AML) patients relapse after initial treatment.
April 25, 2017
Dr. John Dick was recognized for his pioneering research in cancer stem cells with the presentation of the CIHR Gold Leaf Award for Discovery. He was the first scientist in the world to confirm their existence. Better understanding of cancer stem cells has the potential to lead to new treatments, ultimately resulting in improved patient outcomes.
January 26, 2017
The International Society for Stem Cell Research (ISSCR) has honoured Dr. John Dick by selecting him to deliver the 2017 Tobias Award Lecture at the organization’s annual meeting June 14-17 in Boston. The honour, supported by the Tobias Foundation, recognizes promising research into stem cell therapies for haematological conditions.
December 7, 2016
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and is one of the most deadly. Although AML is treated as a single disease, patient response to intensive curative-intent chemotherapy varies. It is currently difficult to predict who will do well with standard treatment, and who will not benefit from standard treatment and might do better enrolling in a clinical trial where they may be offered novel therapies.
December 1, 2016
The base components of DNA – adenine, thymine, cytosine and guanine (commonly referred to as ATCG) are so fundamental to the study of genetics that they are probably familiar to anyone who has taken a high school biology class. Now, one team of researchers has expanded the ‘DNA alphabet’ to help aid in efforts to learn how cancers develop.
August 9, 2016
Patients need access to more stem cells for transplants. Researchers have now identified the genetic switch that could turn on the supply
Researchers at the Princess Margaret Cancer Centre, funded in part by OICR, have found a genetic switch that could be used to develop many more stem cells from the blood found in umbilical cords, a resource that is highly valuable for stem cell transplants but still in short supply.
July 14, 2016
Stem cell scientists discover genetic switch to increase supply of stem cells from cord blood for future clinical use
(TORONTO, Canada – July 14, 2016) – International stem cell scientists, co-led in Canada by Dr. John Dick and in the Netherlands by Dr. Gerald de Haan, have discovered the switch to harness the power of cord blood and potentially increase the supply of stem cells for cancer patients needing transplantation therapy to fight their disease.