Metastases can form in locoregional lymph nodes – a form of progression that portends a worse prognosis but can still be curable – or they can develop in distant organs. Treatments for the latter case are typically considered palliative. It is unknown whether lymph node and distant metastases are only distinguished by their different prognostic implications, or whether the biology underlying their formation is also distinct.
In a new study, published in Nature Genetics, the Naxerova lab at the Center for Systems Biology and collaborators at the Canary Center for Cancer Early Detection at Stanford now show that lymph node and distant metastases develop through different evolutionary mechanisms. Reconstructing the evolutionary histories of dozens of colorectal cancers, the team showed that lymph node metastases are a genetically highly diverse group. Their pronounced heterogeneity indicates that they can be seeded by many different primary tumor sub-lineages. In contrast, distant metastases are homogeneous. They typically resemble each other and have a recent common ancestor, suggesting that fewer primary tumor subclones possess the ability to form lesions in distant organs. These results show that the selective pressures shaping metastasis development in different anatomical sites differ substantially.
Breaking bad habits in cancer therapy
Targeted cancer drugs are designed to kill tumor cells, but can elicit a tumor-protective wound-healing response as the body repairs its dying tissue. In a report published in Science Advances, a team at the MGH Center for Systems Biology and the Massachusetts Institute of Technology collaborated to understand mechanisms of how the immune response to kinase inhibitors could promote drug resistance often seen in patients. Using a computational pipeline to interpret multicellular signaling in the tumors of patients with melanoma or ovarian cancer, the team found that tumor cells adopted a program of wound healing especially related to the role of macrophages in clearing debris from dying cells. This signaling co-amplified between tumor cells and neighboring macrophages to cause drug resistance in a reinforcing feedback loop. To break this destructive cycle, the team formulated a nanotherapy that efficiently accumulated in the phagocytic macrophages of resistant tumors and delivered a toxic payload that blocked resistance.
“CSB work discovers exercise benefits on bone marrow”
The modern life style comes with many dangers. This includes our increased sedentary behavior, as we all spend increasing time sitting: on the office chair, in the car, and on the sofa. This is risky behavior and leads to obesity, myocardial infarction and stroke. A manuscript published in Nature Medicine now describes a new, potentially modifiable pathway how sedentary behavior causes cardiovascular disease. Mice that had access to treadmills in their cages (and run voluntarily up to 6 miles per night), had lower blood stem cell proliferation in their bone marrow. On the flip side, sedentary mice, resembling a large proportion of the American population, work out 20-fold less. As a result, they had higher blood levels of the hormone leptin, which triggered over-production of inflammatory leukocytes, resulting in more atherosclerosis and heart failure. The team also looked at clinical data, including the CANTOS trial. In ~5,000 humans, similar relationships between physical activity, leptin and leukocytes were observed, implicating that the mouse data translate to humans. The next steps involve unbiased drug discovery work, which may not lead to the “exercise pill” but new targets to combat inflammation in cardiovascular disease.
Myeloid cells can promote or limit tumor outgrowth but remain poorly understood. In a study published in Immunity, the Pittet lab at the MGH Center for Systems Biology and the Klein lab at Harvard Medical School teamed up to map myeloid cells at the single cell level in human and mouse lung cancer. They made the following findings: 1) Consistent complexity: the same tumor myeloid populations are repeatedly found across patients, indicating that the myeloid microenvironment within lung tumors is stereotyped. 2) Conservation across species: many myeloid populations are highly conserved across patients and mice, suggesting that studying myeloid cells in mice can help understand the human disease. 3) New therapeutic targets: the map of tumors’ myeloid populations identified in this study points to new targets for cancer immunotherapy.
Researchers say they are closer to solving the mystery of how a good night’s sleep protects against heart disease. In studies using mice, they discovered a previously unknown mechanism between the brain, bone marrow, and blood vessels that appears to protect against the development of atherosclerosis, or hardening of the arteries—but only when sleep is healthy and sound. The discovery of this pathway underscores the importance of getting sufficient, quality sleep to maintain cardiovascular health and could provide new targets for fighting heart disease, the leading cause of death among women and men in the United States. In a study published in Nature, the Swirski Lab at the MGH Center of Systems Biology identified a mechanism by which a brain hormone controls production of inflammatory cells in the bone marrow in a way that helps protect the blood vessels from damage. This anti-inflammatory mechanism is regulated by sleep, and it breaks down when you frequently disrupt sleep or experience poor sleep quality.
The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways, how our bodies handle nutrients depends on strategically-positioned metabolic sensors that link a meal’s intrinsic nutritional value with intermediary metabolism. In a study published in Nature, the Swirski Lab at the MGH Center of Systems Biology identifies a subset of immune cells in the gut that modulates metabolism. The team shows that gut intraepithelial T leukocytes (IELs) modulate systemic metabolism. Mice lacking natural IELs are metabolically hyperactive and, when fed a high fat and sugar diet, resist obesity, hypercholesterolemia, hypertension, diabetes, and atherosclerosis. The phenomenon depends on the incretin GLP-1, which IELs normally control via IEL GLP-1 receptor expression. While its function may prove advantageous when food is scarce, overabundance of diets high in fat and sugar render this metabolic checkpoint inimical to health.
The anti-PD-1 immune checkpoint blocker can induce sustained clinical responses in some patients. This drug is used to release the “brakes” on T cells but how it functions in vivo remains incompletely understood. In a study published in Immunity, the Pittet Lab at the MGH Center for Systems Biology uncovers that effective antitumor responses to anti-PD-1 therapy requires a subset of tumor-infiltrating dendritic cells, which produce interleukin 12 (IL-12) and apply “gas” to fuel the antitumor reaction. The findings may lead to new treatment strategies that benefit more patients.
Modern oncology relies on molecular assessments of tumor tissue to develop new therapeutic combinations and select optimal treatments for individual patients. Conventional approaches to cellular fluorescence imaging allow for visualization of just 3-4 proteins at a time, limiting the amount of information we can gain from precious patient biopsy samples. In a new study published in Nature Communications, researchers at CSB developed an approach that uses antibody-DNA conjugates to efficiently “cycle” through the detection and quantification of multiple proteins of interest, dramatically increasing the number of pathways/targets that can be imaged from a single biopsy. This technique allows scientists/physicians to directly visualize complex protein signatures in the biopsied cells and has important implications for understanding how drug therapies affect patients’ individual tumors.
White blood cells are our key defenders against infection, however if oversupplied, they may turn against us. Neutrophils are made in the bone marrow where they arise from hematopoietic stem cells. The bone marrow is distributed over many bones in our bodies, and the current thinking implies that the supply of leukocytes distributes evenly throughout the body. In work published in Nature Neuroscience, we describe that the skull marrow assumes a special role in inflammatory diseases of the CNS. Its proximity to the brain leads to a preferential supply of neutrophils. We detected a previously unknown shortcut that neutrophils use on their way from skull marrow cavities towards the central nervous system. Rather than traveling through the general blood circulation, leukocytes produced in skull bone marrow migrate through channels that directly connect the skull marrow with the meninges the brain is wrapped in. The channels exist in mice and humans.
Automating cellular diagnostics could have far reaching impact in healthcare. Cells – often obtained by aspirations, biopsies, swabs or through body fluids – typically require sophisticated instrumentation and time consuming experts analysis to provide diagnoses. The CSB engineering team has now developed a highly sensitive platform powered by digital imaging and artificial intelligence to automate such painstaking analyses. Moreover this platform is affordable ($~200) and portable, thus uniquely suited for point-of-care diagnostics in low and middle income countries (LMIC). A recent study published in Nature Biomedical Engineering highlights the first clinical trial for lymphoma diagnostics.
Tumor-associated macrophages (TAM) are abundant in many cancers and often display an immune-suppressive phenotype that promotes tumor growth and resistance to treatment. Researchers at CSB have now developed a TAM targeted nanoparticle loaded with a toll-like receptor agonist which re-programs TAMs to support the immune-system’s fight against cancer. As a monotherapy, administration of the drug-loaded nanoparticle led to efficient drug delivery to TAMs, re-programming of TAMs to an immune-supportive phenotype, and controlled tumor growth. Importantly, the strategy worked synergistically in combination with checkpoint therapy (anti-PD1), dramatically improving response rates even in tumors resistant to treatment by anti-PD1 alone. These findings demonstrate the ability of rationally engineered drug–nanoparticle combinations to efficiently modulate TAMs to better sensitize the tumor microenvironment to standard checkpoint therapies.
Tumors are often infiltrated by diverse immune cell types, some of which remain largely unexplored. In a study published in Science, the Pittet lab at the MGH Center for Systems Biology uncovers a new type of neutrophil that promotes lung cancer. The production of these neutrophils involves an unexpected remote crosstalk between tumors and bones: lung tumors remotely activate osteoblasts; in turn, those bone cells shape immunity by supplying tumors with cancer-promoting neutrophils. The findings open new avenues for cancer immunotherapy.
Ischemic heart disease is the most common cause of death in the world and it begins with a heart attack. When cells die in the heart, the immune system enters the dead tissue, clears debris, stabilizes and repairs the heart wall. But what is it about dying cells in the heart that is so immune stimulatory? To answer this, researchers at CSB looked deep inside thousands of individual cardiac immune cells and mapped their individual transcriptomes using a method called single cell RNA-Seq. This lead to the discovery that after a heart attack, DNA from dying cells masquerades as a virus and activates an ancient antiviral program called the type I interferon response in specialized immune cells that they term interferon inducible cells (IFNICs). When investigators blocked the interferon response, either genetically or with a neutralizing antibody given after the heart attack, there was less inflammation, less heart dysfunction, and improved survival. Their findings, published in Nature Medicine, unmask a new potential therapeutic opportunity to prevent heart attacks from progressing to heart failure in patients.
More than 50 million Americans display food reactions. Each year there are an estimated over 20,000 food allergy-related emergency department visits in the United States, including 90,000 cases of anaphylaxis. The best way to manage food allergy is to avoid products that contain allergen. But avoidance isn’t always possible because food can be mislabeled or cross-contaminated.
Meet iEAT (integrated Exogenous Antigen Testing) a $40 portable allergen-detection system that consists of a disposable kit to extract allergens from food and an electronic keychain analyzer for allergen detection. In less than 10 minutes, the iEAT completes food analyses and sends the results to a cloud server. The prototype was used to detect five model allergens from wheat, peanuts, hazelnuts, milk and egg white. Testing on food items from local restaurants revealed unexpected findings such as gluten in “gluten-free” dishes and egg protein in beer. The technology is being expanded to detect additional allergens, pesticides and environmental hormones.
Macrophages, immune cells in our body, have a long to-do list. They defend us from bacteria, are essential in wound healing, keep the heart beating and perform other vital tasks. In a new twist, these cells are now shown to dramatically accumulate on the outside of cancer microvessels following radiation therapy. There, they elicit dynamic and focally localized bursts of capillary leaks. This in turn enhances drug delivery, especially of nanomaterials. These new insights have implications for the design of next-generation tumor targeted nanomaterials and clinical trials for adjuvant strategies.
Pancreatic ductal adenocarcinoma is one of the deadliest types of tumors, in part because it is usually detected at a late stage. To facilitate the diagnosis of this tumor, researchers at CSB have developed a multiplexed nanoplasmonic assay to analyze extracellular vesicles in blood of patients. While some blood biomarkers have previously been proposed, none of them have proven sufficiently accurate in clinical practice. We have now identified a new five-marker signature that yielded the most accurate diagnosis in a large cohort of patient samples.
Immunotherapy and especially immune checkpoint blockers (ICBs) are revolutionizing how we treat many cancers. Designed to activate the immune system, these drugs can be extraordinarily effective in some patients. But progress has been slowed by our limited understanding of why ICBs work well in some cancers and patients but not in others. Now, Mikael Pittet and colleagues have used molecular imaging to track ICBs in real time and at high resolution within tumors. Their study, published in Science Translational Medicine, uncovers a previously undiscovered mechanism of treatment resistance, which can be overcome with additional chemical modifications.
Cardiac macrophages charging ahead
While we knew for a while that the healthy heart contains tissue resident macrophages, these cells’ organ specific functions were unknown. Triggered by a serendipitous finding of ECG abnormalities during a cardiac MRI scan of a mouse after macrophage ablation, a CSB team of investigators now describes previously unknown electrical properties of macrophages. When coupled to myocytes via gap junctions, macrophages depolarize in sync with conducting cells. In a sink-source relationship, electric current flows back and forth between macrophages and cardiomyocytes. Macrophages influence conduction through the atrioventricular node, the electrical connection between the heart’s chambers. When macrophages are manipulated, the flow of electricity slows down, and may even cease altogether. Such a condition requires pacemaker treatment in humans. These surprising findings, published in Cell, jolt the field of electrophysiology and may lead to new therapeutic opportunities for patients with cardiac arrhythmias. The collaborative effort was spearheaded by teams at MGH but also involved investigators at the BWH and in Freiburg, Germany.
Tiny nanoparticles hunt for macrophages
Macrophages are white blood cells that can turn against us in atherosclerosis. Instead of cleaning up tissue as usual, they attack the arterial wall and destroy its architecture. The resulting stoppage of blood flow causes myocardial infarction and stroke. An entire field of research focuses on understanding these cells, and how to stop them from becoming turn coats. Until now, it was not even possible to detect them reliably in patients. In a recent Nature Communications report, a modified polyglucose nanoparticle (18F-Macroflor) was developed for imaging macrophages by PET. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. This work marks an important step towards a clinical tool to non-invasively monitor macrophage biology in patients. Such an imaging tool can then be used to spot danger spots in several diseases, and test new macrophage-targeted therapeutics while directly watching the cells.
Iron gives blood its red color. The metal is essential to life, but it can be toxic because of its oxidative properties. Remarkably, we receive relatively little of our daily iron needs through diet. By far the majority of the iron we need is recycled. According to current thinking, as red blood cells age, large phagocytes residing in the spleen capture them, digest the cell structures, and recycle iron. A new paper from CSB published in Nature Medicine shows that most red blood cell disposal actually occurs in the liver, especially when demands for disposal increase (as they do in many physiologic and pathophysiologic situations). Moreover, specialized white blood cells consume old red blood cells in the circulation before migrating to the liver to shuttle iron for storage and new red blood cell production. The process buffers against dangerous fluctuations in iron availability, keeping the body in balance.
Quintuple-target RNAi: hitting five targets at once
Vascular endothelial cells express five adhesion molecules to recruit leukocytes from the blood stream: E- and P-selectin, ICAM-1 and -2, and VCAM-1. In atherosclerosis, activated endothelial cells express high levels of these signals, thus expanding the number of neutrophils and monocytes that migrate from blood into a growing plaque. After myocardial infarction, the adhesion molecule expression increases even further due to higher autonomic nervous activity. A collaborating team of groups at MIT and MGH now used a new class of nanoparticles with high avidity to endothelial cells to decrease endothelial cell adhesion molecule expression. The polymeric nanoparticles made of low-molecular-weight polyamines and lipids were loaded with 5 distinct siRNAs silencing the expression of all adhesion molecules. Multiple gene silencing was enabled by exquisite silencing efficiency after nanoparticle delivery. Hitting five targets at once, the therapy reduced recruitment of leukocytes to atherosclerotic plaques in mice, dampening vascular wall inflammation and making plaques smaller. Furthermore, RNAi decreased migration of leukocytes into infarcted myocardium, improving the recovery after ischemia. Such a strategy may help to prevent reinfarction and heart failure in high-risk patients with acute MI.
Rapid and efficient diagnosis of bacterial infection is critical in combating infections, esp. in the hospital setting where drug resistnace to antibiotics is on the rise. CSB investigators have developed a new device to shorten the diagnosis of bacterial infection to less than 2 hours. The “PAD” system (short for polarization diagnostics) is a combination of optical read-outs of genetic bacterial information and can ultimately performed in a physician’s office at low cost.
Macrophages are mostly viewed as tumor-promoting cells. They can infiltrate solid tumors in high numbers, and their presence at the tumor site is often associated with decreased patient survival. However, much less is known about macrophages located outside the tumor stroma. Mikael Pittet and colleagues now show that a population of lymph node macrophages, called subcapsular sinus (SCS) macrophages, unexpectedly protects against melanoma. The study was published in Science on March 17, 2016
Novel immune checkpoint blockade therapies can be extraordinarily effective but may benefit only the minority of patients whose tumors are pre-infiltrated by antitumor immune cells called CD8+ T cells. In a study published in Immunity, the Pittet lab at MGH Center for Systems Biology reports that rationally selected immunogenic chemotherapy can convert tumor microenvironments lacking T cells into ones displaying antitumor T cell immunity. This process makes unresponsive tumors sensitive to immune checkpoint blockade therapies and consequently raises hope to feasibly expand the proportion of human cancers responding to these therapies.
Nanoparticles promise to deliver toxic chemotherapeutics more safely and efficiently to solid tumors, but clinical responses to such treatments have been mixed: some patients respond extremely well while others do not. Using advanced imaging techniques, researchers at CSB have discovered a way to repurpose FDA-approved magnetic nanoparticles for predicting how effectively nanomedicines can accumulate in tumors. Published in Science Translational Medicine, this “companion diagnostic" approach suggests that clinical imaging can be used to select patients most likely to benefit from the most advanced nanomedicine treatments.
Macrophages act as drug delivery depots of nanomedicines
Solid tumors often contain large numbers of immune cells including macrophages that feed cancer growth and metastasis. CSB researchers discovered that these tumor associated macrophages can be co-opted by nanomaterials to serve as drug depots, gradually delivering chemotherapy to neighboring cancer cells. Driven by new intravital imaging technology and published in Nature Communications, this research presents a new paradigm for therapeutic design and for selecting patients into clinical trials.
Bone marrow stem cells are alerted to heart attack.
The white blood count is one of the most frequently ordered medical tests, reflecting its clinical value. In patients with heart disease, leukocytosis closely correlates with survival. We increasingly understand why: inflammatory monocytes and macrophages, when overproduced, damage the arterial wall and vital organs such as the heart after myocardial infarction. We have surprisingly limited understanding of mechanisms leading to increased leukocyte count in cardiovascular patients. Blood cells, including inflammatory monocytes, are made in the bone marrow and ultimately derive from pluripotent hematopoietic stem cells. Until now it was unknown which bone marrow cells expand in acute myocardial infarction. Recent work published in Cell Stem Cell identified a subpopulation of progenitors as the most upstream activation point after MI. The surface marker CCR2 identifies, in mice and in humans, the cells that sit almost at the very top of the hematopoietic tree as particularly responsive to an injury of the heart. The myeloid translocation gene 16 regulates the emergence of these highly active stem cells, and may provide a therapeutic target to dampen leukocyte production that could otherwise jeopardize resolution of inflammatory activity in cardiovascular organs. The interdisciplinary work united cardiovascular, immunology, imaging and hematology scientists in a collaborative effort to tease out cross talk between the injured heart and blood stem cells.
With their ubiquitous presence and superb computation power, smartphones now bring unprecedented opportunities to realize mobile healthcare. Reported in PNAS, CSB researchers have developed a new smartphone-based system, D3 (digital diffraction diagnosis), for on-the-spot molecular detection. This system, complete with a custom App, was used for cervical cancer screen and diagnosing aggressive lymphomas, prevalent cancers in low and middle-income countries.
The complication of an infection known as sepsis (or “blood poisoning”) is extremely dangerous, claiming up to half a million lives in the United States every year. A study from the Swirski lab has shown that a growth factor called interleukin-3 (IL-3) amplifies inflammation in sepsis and potentiates septic shock, the most severe form of sepsis. The authors show that IL-3 induces the emergency production of inflammatory monocytes and neutrophils, which are sources of the hallmark cytokines that comprise a lethal cytokine storm. A subset of B-1 B cells, discovered in the Swirski lab and named IRA B cells, are abundant sources of IL-3 in sepsis. Patients diagnosed with sepsis with high IL-3 in their blood die more often than those containing low IL-3.
When our drugs don’t work.
Eribulin was developed as a potent anticancer agent, but it fails in many patients for unknown reasons. In a recent study, CSB researchers used microscopic imaging in tumors to show that resistance is primarily due to MDR1-mediated drug efflux. It was discovered that a new nano-encapsulated MDR1 inhibitor was able to restore drug efficacy. These studies show that in vivo imaging is a powerful strategy for elucidating mechanisms of drug resistance in heterogeneous tumors and for evaluating strategies to overcome this resistance.
For decades, doctors knew that chronic stress is bad for you. Atherosclerosis has been nicknamed a “manager’s disease” for this reason. Previously, we thought this is because of heightened blood pressure, and its direct actions on the blood vessel wall. The study by Heidt and Sager found that psychosocial stress activates bone marrow stem cells, which in turn triggers overproduction of inflammatory leukocytes, including neutrophils and monocytes. These leukocytes are more numerous in blood and accumulate in atherosclerotic lesions, putting the individual at higher risk for myocardial infarction and stroke.
Tiny holes enable big measurements
A new technology developed at CSB allows profiling of small subcellular structures such as exosomes. The technology uses tiny gold grids studded with nanoholes in array format. Each of the holes has been modified with different antibodies. Biomarkers interacting with these tiny nano holes change the light properties (nano-plasmons), an effect which can optically detected. This technology (”nPLEX”) will allow high-throughput analysis of a number of clinically important biomarkers.
Extracting maximal information from minimal, easily acquired samples is the holy grail for patient monitoring in clinical trials. Until now, invasive or expensive procedures have been the only means of gaining accurate information regarding disease status and treatment response. Now, a new technology developed at the CSB, published in Science Translational Medicine holds promise for revolutionizing clinical monitoring by allowing vast amounts of proteomic information to be obtained from minute samples.