In 2020, an estimated 10 million people lost their lives to cancer. This devastating disease is underpinned by changes to our DNA—the instruction manual for all our cells.
It has been 20 years since scientists first unveiled the sequence of the human genome. This momentous achievement was followed by major technological advances that allow us to today read the layers of information of our DNA in enormous detail—from the first changes to DNA that occur as a cell becomes cancerous to the complex microenvironments of advanced tumors.
Now, to accelerate discoveries for cancer patients, we need new ways to bring together the different types of complex data we generate to provide new biological insights into cancer evolution.
For today's issue of Science, my colleagues Professor Toshikazu Ushijima, Chief, Epigenomics Division, National Cancer Center Research Institute (Japan), Prof Patrick Tan, Executive Director, Genome Institute of Singapore and I were invited to review the cancer insights we can currently obtain from analyzing DNA in its full complexity and define the future challenges we need to tackle to yield the next step-changes for patients.
A team led by researchers at Weill Cornell Medicine, the New York Genome Center, Harvard Medical School, Massachusetts General Hospital and the Broad Institute of MIT and Harvard has profiled in unprecedented detail thousands of individual cells sampled from patients' brain tumors. The findings, along with the methods developed to obtain those findings, represent a significant advance in cancer research, and ultimately may lead to better ways of detecting, monitoring and treating cancers.
Researchers have developed a tool that integrates a variety of molecular data from patients and tumors, with the goal of guiding precision medicine.
A promise of precision cancer medicine is for oncologists to tailor treatment based on a patient's unique molecular profile. In practice, however, interpreting the vast array of data points which make up a person and their cancer is challenging, and only made more difficult as oncologists begin to consider additional complex features. Databases and analytical tools that oncologists might use typically focus on individual alterations in the somatic, or uninherited, protein-coding regions of the genome; they generally do not include other important types of genetic data such as inherited variation or somatic fusions in genes. Scientists and oncologists also typically consider these features in isolation, rather than together or alongside traits that characterize a tumor globally.
Scientists Find a New Way To Reverse Immune Suppression in Cancer Tumors
TOPICS:CancerCell BiologyCornell UniversityLung CancerLungs https://scitechdaily.com/scientists-fin ... er-tumors/
By Weill Cornell Medicine October 3, 2021
Immunofluorescent Lung Images Radiation Treatment
Malignant tumors can enhance their ability to survive and spread by suppressing antitumor immune cells in their vicinity, but a study led by researchers at Weill Cornell Medicine and NewYork-Presbyterian has uncovered a new way to counter this immunosuppressive effect.
In the study, published on September 20, 2021, in Nature Cancer, the researchers identified a set of anti-immunosuppressive factors that can be secreted by cells called club cells that line airways in the lungs. They showed in a mouse model of lung cancer that these club cell factors inhibit highly potent immunosuppressive cells called myeloid-derived suppressor cells (MDSCs), which tumors often recruit to help them evade antitumor immune responses.
The inhibition of the MDSCs led to an increase in the number of antitumor T cells at the tumor site, and greatly improved the effectiveness of FDA approved PD1 immunotherapy.
“These club cell-secreted factors are able to nullify immune suppressor cells that otherwise help tumors escape an effective antitumor response,” said co-senior author Dr. Vivek Mittal, director of research at the Neuberger Berman Lung Cancer Center and the Ford-Isom Research Professor of Cardiothoracic Surgery at Weill Cornell Medicine. “We’re excited by the possibility of developing these club cell factors into a cancer treatment.”
A University of Alberta researcher has discovered how two signaling molecules recruit immune cells known as "killer" T cells to a specific type of colon cancer with more favorable patient outcomes. The finding may represent a therapeutic strategy to target other types of cancers.
Kristi Baker, assistant professor in the Department of Oncology, examined tumors from patients with mismatch repair deficient colorectal cancer, a type that affects about 10 to 15 per cent of patients. While 85 per cent of colorectal cancers come from polyps, the mismatch repair deficient subset is developed through a different set of mutations.
"All cancer cells have a lot of mutations, but this particular group has a significantly higher number—almost tenfold as much as some of the other cancers," said Baker, who is also a member of the Cancer Research Institute of Northern Alberta and the Women and Children's Health Research Institute.
That higher number of mutations is what gives patients with the mismatch repair deficient tumors more positive outcomes in general. The immune system can sometimes overlook tumors because they look so similar to normal cells, so they aren't recognized as something foreign that needs to be attacked. But the higher number of mutations in mismatch repair deficient tumors means they're very visible to the immune system.
Colorectal cancer is projected to claim 53,000 lives in the United States this year alone, and as with most cancers, the disease is deadliest when it metastasizes. It follows that the most effective way to control it would be a drug that targets metastasis itself—preventing cancer cells from breaking off the primary tumor, or reining in rogue cells before they spread throughout the body and seed secondary tumors.
Now, a new study identifies a small molecule that could, in the future, be administered alongside standard chemotherapies to stave off colorectal cancer metastasis. The research, published in Science Advances, demonstrated how the compound, named RGX-202, foils a key pathway that cancer cells rely upon to hoard energy, thereby killing them and shrinking tumors in mice.
The findings have already led to a clinical trial in humans and may eventually give rise to a novel therapy that increases survival rates for multiple gastrointestinal cancers.
"Colorectal cancer is one of the top causes of cancer-related mortality," says Rockefeller's Sohail Tavazoie, head of the Elizabeth and Vincent Meyer Laboratory of Systems Cancer Biology. "We've found a critical pathway that promotes colorectal cancer metastasis and a novel therapeutic that appears to inhibit it."
A team of clinicians and scientists from the National Cancer Centre Singapore (NCCS), Singapore General Hospital (SGH) and A*STAR's Genome Institute of Singapore (GIS) has identified a novel method to treat triple-negative breast cancer (TNBC). They discovered that cancer cells switch between different cell states and are able to change from being less aggressive ("epithelial") to being more aggressive ("mesenchymal"), and vice versa. By converting highly aggressive cancer cells to become less aggressive, physicians can prime tumors to respond better to chemotherapy, which works to eliminate cancer cells. This discovery has led to the launch of a three-year long human clinical trial, BEXMET (Bexarotene-induced Mesenchymal-Epithelial Transition), to investigate this unconventional approach to treating TNBC.
TNBC is more aggressive than other breast cancer sub-types, with limited treatment options and a poor prognosis. TNBC tests negative for estrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor receptor-2 (HER2), hence the reference to 'triple-negative' in its name. This also means that treatments targeting ER, PR and HER2 are not effective. For that reason, chemotherapy is still the mainstay standard treatment for TNBC.
The development of novel oncology drugs is costly, and affordability and accessibility can be a challenge. The concept tested by the NCCS, SGH and GIS team involves altering cancer cell states so that they are more susceptible to currently available chemotherapy. This may be a cost-effective way to treat TNBC, with the potential to treat a wider range of other cancers.
A new study published in Nature has found that a single sulfatase contributes to the degradation of mucus that protects the intestinal lining, potentially leading to inflammatory bowel disease and colorectal cancer.
The human gut microbiota significantly impacts several aspects of intestinal health and disease, including inflammatory bowel disease (IBD) and colorectal cancer. In the colon, secreted mucus creates a barrier that separates gut microorganisms from the lining of the intestine, preventing close contact that can lead to these conditions.
Some gut bacteria are able to utilize mucin glycoproteins, the main mucus component, as a nutrient source. However, it remains unclear which bacterial enzymes initiate degradation of the complex O-glycans found in mucins.
Despite the critical roles of sulfatases in many biological processes, including diseases, the researchers from a group of Universities including the University of Liverpool, University of Gothenburg, and the University of Michigan aimed to address the significant knowledge gap regarding their specificity and mechanisms.
A major component of colonic mucus is mucin 2, a glycoprotein. Mucin glycosylation is variable along the gastrointestinal tract, with an increase in sulfation in the colon, especially in the distal colon.
To degrade the complex O-glycans found in mucins, some human gut bacteria
have evolved complex arsenals of degradative enzymes that include sulfatases.
Pairing a newly developed gel with immunotherapy that was delivered to post-surgical mouse brains with glioblastoma, a highly malignant and deadly cancer, improved the immunotherapy's effectiveness, report researchers from the University of North Carolina Lineberger Comprehensive Cancer Center and colleagues. The findings appeared Oct. 6, 2021, in Science Advances.
The researchers used CAR-T cell (chimeric antigen receptor-T cell) immunotherapy, which involves harvesting immune-system T cells from a patient and genetically re-engineering them in the lab to recognize targets on the surface of cancer cells. In this mouse study, the CAR-T cells and gel were placed to fill in the area where a glioblastoma tumor had just been surgically removed. Previous studies have shown that administering T cells alone has produced limited benefit.
Glioblastoma is an aggressive tumor that can form quickly in the brain and is diagnosed most often in people in their sixties. Only 40 percent of people live for one year after diagnosis; just 17 percent survive for two years. Surgery is the first treatment used but presents many challenges in removing the tumor while also allowing for wound healing.
"We developed a gel made of fibrin, a protein most often associated with helping blood to clot. Applying a gel substance to an area of the brain to aid CAR-T cell therapy is unique in glioblastoma treatment," said Edikan Ogunnaike, Ph.D., a biomedical engineer at UNC and first author of the article. "The gel aided CAR-T cell distribution in the brain by acclimating the T cells to the post-surgical wound environment while also stopping the tumor from recurring."
When it comes to cancer detection, size matters. Traditional diagnostic imaging cannot detect tumors smaller than a certain size, causing missed opportunities for early detection and treatment. Circulating tumor exosomes are especially small cancer biomarkers and easy to miss. These nanovesicles are composed of molecules that reflect the parental cells. But, because they are tiny (~30-150nm in diameter) and complex, the precise detection of exosome-carried biomarkers with molecular specificity is elusive.
Until now, reports Wei-Chuan Shih, professor of electrical and computer engineering at the University of Houston Cullen College of Engineering, in IEEE Sensors journal.
"This work demonstrates, for the first time, that the strong synergy of arrayed radiative coupling and substrate undercut can enable high-performance biosensing in the visible light spectrum where high-quality, low-cost silicon detectors are readily available for point-of-care application," said Shih. "The result is a remarkable sensitivity improvement, with a refractive index sensitivity increase from 207 nm/RIU to 578 nm/RIU."
Immune checkpoint inhibitors, which unleash the immune response against tumor cells, have revolutionized cancer treatment; however, the medications aren't effective in a large number of patients, including those with colorectal cancer. New research published in PNAS that was led by investigators at Massachusetts General Hospital (MGH) and the University of Geneva (UNIGE) provides insights on why some types of colorectal cancer don't respond to immune checkpoint inhibitors and offers a strategy to overcome their resistance.
"Colorectal cancer is the second leading cause of cancer-related death in the United States and worldwide," says senior and co–corresponding author Rakesh K. Jain, Ph.D., director of the E.L. Steele Laboratories for Tumor Biology at MGH and the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School (HMS). "A major cause of mortality in patients with colorectal cancer is the development of liver metastases, which is the spread of cancer to the liver."
A researcher at the University of Missouri School of Medicine has discovered an enzyme that plays a key role in the ability of cancer cells to resist drug treatment.
Immunomodulatory drugs like thalidomide, lenalidomide and pomalidomide have improved the treatment of patients with multiple myeloma and other blood cancers. But almost all patients eventually develop resistance to these therapies.
Principal investigator Thang Van Nguyen, DVM, Ph.D., an assistant research professor in the Center for Precision Medicine, discovered that a protein called USP15 is highly expressed in cancer cells that become resistant to the standard immunomodulatory drugs.
"This USP15 protein protects the cancer cells from destruction by removing ubiquitin tags placed on the cells by the immunomodulatory drugs," Nguyen said. "Those tags initiate the cell degradation process. But if those tags are removed by USP15, the cancer cells will continue to grow and multiply."
Nguyen believes testing multiple myeloma patients for USP15 will help determine if a patient will be resistant to immunomodulatory drug therapy. That knowledge could lead to a more precise, customized treatment.
While substantial strides have been made against some types of childhood cancers, high-grade gliomas still lack effective treatments.
Thirty to 60% of these pediatric brain tumors bear mutations in the gene H3F3A. This gene contains the encoded blueprint for histone H3.3, which plays an important role in the structure of chromatin. One of these mutations is known to scientists as H3.3G34R/V—meaning the amino acid glycine that's normally found at position 34 has been replaced by either an arginine or a valine.
Now an international research team led by the University of Michigan Health Rogel Cancer Center has found a small-molecule inhibitor that was able to suppress tumor growth in animal models of this glioma—offering new hope toward developing therapies for pediatric patients. Their findings appear in Science Translational Medicine.
"These tumors tend to occur in slightly older children than some of the more well-known types of childhood glioma—usually between the ages of 10 and 18," said senior study author Sriram Venneti, M.D., Ph.D., the Al and Robert Glick Family Research Professor of Pediatrics in the Department of Pathology at Michigan Medicine. "And the prospects remain quite dismal due to a lack of effective treatments."
In a first-in-world clinical trial, researchers at Sunnybrook Health Sciences Centre in Toronto, Canada, have demonstrated that magnetic resonance (MR)-guided focused ultrasound can be used to safely deliver antibody therapy to breast cancer that has metastasized to the brain.
In this Phase I clinical trial for Her2-positive breast cancer patients, the Sunnybrook team captured images of the antibody therapy, trastuzumab (or Herceptin), precisely targeting tumors in the brain after using Insightec's Exablate Neuro focused ultrasound device to temporarily and non-invasively open the blood-brain barrier (BBB) and enable intravenous trastuzumab to more effectively access tumor sites.
Antibody therapies can help the immune system fight cancer cells, and they are often used in combination with radiation and chemotherapy. However, the BBB presents a challenge when attempting to target sites in the brain. The BBB is a layer of cells lining blood vessels that protects the brain from viruses, bacteria, and other toxins—but it can also prevent therapeutics, such as trastuzumab, from reaching the brain in high enough concentrations to be effective.
"This is the first visual confirmation that focused ultrasound can improve the delivery of targeted antibody therapy across the BBB," says Dr. Nir Lipsman, the study's principal investigator and director of the Harquail Centre for Neuromodulation at Sunnybrook. "These are preliminary, but very promising results, that with continued research, have implications well beyond brain cancer for other neurological conditions, including Parkinson's disease and Alzheimer's, where the blood-brain barrier poses a challenge to drug delivery."
Lymphomas can turbo-charge their ability to proliferate by crowding growth-supporting enzymes into highly concentrated compartments within tumor cells, according to a study led by researchers at Weill Cornell Medicine.
The preclinical study, published Sept. 3 in Cancer Research, demonstrated that certain aggressive B-cell lymphomas use a protein-shepherding molecule called HSP90 to form and maintain these densely packed metabolic compartments, which are full of enzymes that synthesize amino acids and other cellular building blocks.
The researchers found that they could use an existing experimental drug that inhibits HSP90 to break up these metabolic compartments and slow lymphoma metabolism in lab-dish and animal studies.
"This strategy looks very promising as a way to treat aggressive lymphomas and also sensitize them to other therapies—we're hoping to test it soon in lymphoma patients," said senior author Dr. Leandro Cerchietti, associate professor of medicine in the Division of Hematology and Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
By combining computational and experimental approaches, University of Pittsburgh School of Medicine and Prairie View A&M University researchers identified cancer drugs that show promise for treating pulmonary hypertension, or PH, a rare and incurable lung disease.
Published today in Science Advances, the study used a new algorithm to identify candidate cancer drugs for PH. Two of these compounds improved markers of the disease in human cells and rodents. The findings support broader use of this drug-repurposing platform for other non-cancerous conditions that don't yet have effective treatments.
"Repurposing drugs can cut down the time and cost of developing treatments for rare diseases, which historically don't receive much investment into research and drug development," said senior author Stephen Chan, M.D., Ph.D., professor of medicine and director of the Vascular Medicine Institute at Pitt and UPMC. "Pulmonary hypertension is an example of a rare disease where there is an unmet need for new treatments, given its devastating consequences. We developed this pipeline to rapidly predict which drugs are effective for PH and get these treatments to patients faster."
Pulmonary hypertension is a type of high blood pressure that occurs in the vessels that transport blood from the heart to the lungs. As the disease progresses and the heart must strain harder against these high pressures, it can lead to heart failure, multi-organ dysfunction and death. PH affects people of all ages but hits young women more often than men.
One of these young women is Allison Dsouza, a 24-year-old nurse who not only lives with the condition herself but also treats PH patients in the UPMC Lung Transplant Program. She was diagnosed with PH as a high school senior after she started having trouble walking to her car and doing hobbies like horseback riding. According to Dsouza, she was the sickest patient with the highest lung pressures that her doctors had seen.
A new study led by Yale Cancer Center researchers shows that the enzyme KDM5B suppresses anti-melanoma immunity. These findings could help develop a new treatment strategy to benefit patients with melanoma and other cancers, especially those who do not respond to current therapies. The research is published online today in the journal Nature.
"These results are exciting as we discovered fundamental roles of some poorly studied genetic elements in immune responses and identified a new way to stimulate the ability of our immune system to fight cancer," said Qin Yan, Ph.D., Associate Professor of Pathology and Director of the Epigenetics Program in the Department of Pathology and a member of Yale Cancer Center. "In addition, we showed that this method can be used to overcome the resistance to current cancer immunotherapies."
In the study, researchers show depletion of the protein KDM5B, which is critical for melanoma maintenance and drug resistance, induces robust adaptive immune responses, and enhances responses to immune checkpoint blockade. KDM5B partners with SETDB1, a protein coding gene, to repress the expression of certain genetic elements such as MMVL30. Expression of these genetic elements stimulates RNA and DNA sensing pathways and subsequent interferon responses, leading to tumor rejection and immune memory.
Yan and his team have been working on the roles of KDM5 proteins in development and cancer for many years. These studies began when researchers sought to understand the roles of KDM5B in melanoma in close collaboration with the lab of fellow Yale researcher Marcus Bosenberg, MD, Ph.D., a co-corresponding author of the study. Resources and expertise provided by the Yale Center for Immuno-Oncology and the Yale SPORE in Skin Cancer were critical for this research.
Lung cancer can be elusive to spot and difficult to treat because the markers for it are found in other tissues, too. Now, University of Illinois Urbana-Champaign researchers have developed a finely tuned molecular agent that can target lung and other cancer cells for imaging and treatment.
In a paper published in the journal Nature Chemistry, the researchers described the molecule's ability to target lung cancer cells, image them and deliver targeted treatment in cultures of human cancer cell lines as well as in live mice.
The researchers picked a surprising biomarker to target: glutathione, a molecule naturally produced in tissues throughout the body but expressed in greater quantities in lung cancer. Because of its ubiquity, they said, it has not been a good target for treatments such as chemotherapy.
"One of the biggest issues with developing diagnostic tools or targeted drugs is off-target effects," said Illinois chemistry professor Jefferson Chan, who conducted the study with graduate student Melissa Lucero. "When you give a patient a chemotherapeutic, it's kind of an arms race: You're killing the cancer cells, but you're also killing the rest of the body because so many things are similar. We used a unique chemistry approach to tune the reactivity of our molecule, so that we're targeting what would typically be considered a bad biomarker."
Writing in EMBO reports, researchers at University of California San Diego School of Medicine and Moores Cancer Center at UC San Diego Health describe how a pair of fundamental genetic and cellular processes are exploited by cancer cells to promote tumor survival and growth.
The findings appear in the October 26, 2021 issue of the journal, a publication of the European Molecular Biology Organization.
Cancer is driven by multiple types of genetic alterations, including DNA mutations and copy number alterations ranging in scale from small insertions and deletions to whole genome duplication events.
Collectively, somatic copy number alterations in tumors frequently result in an abnormal number of chromosomes, termed aneuploidy, which has been shown to promote tumor development by increasing genetic diversity, instability and evolution. Approximately 90 percent of solid tumors and half of blood cancers present some form of aneuploidy, which is associated with tumor progression and poor prognoses.
In recent years, it has become apparent that cells cohabiting within a tumor microenvironment are subject not only to external stressors (mainly of metabolic origin, such as lack of nutrients), but also to the internal stressor aneuploidy. Both activate a stress response mechanism called the unfolded protein response (UPR), which leads to an accumulation of misfolded proteins in the endoplasmic reticulum (ER) of cells—an organelle that synthesizes proteins and transports them outside the cell.
