In the effort to overcome cancer, whether in general or with specific tumor types, many approaches are in play in therapeutic research and development. That makes sense, as cancer is such a heterogenous entity—not one thing, but a multitude of enemies with different strengths and weaknesses.
But in the end, tumors are collections of cancerous cells, and understanding cellular biology and cellular responses is a key aspect. Many other avenues of research intersect with cellular biology, from genomics and proteomics to immunotherapies and microbiome tactics.
So let’s explore some recent research efforts in which the cellular environment is a focus of the work.
Single-cell epigenomic data yields insights
As cancer cells evolve, many of their genes become overactive while others are turned down, all of which are changes that help tumors grow out of control and, as noted by the Massachusetts Institute of Technology (MIT), “become more aggressive, adapt to changing conditions and eventually lead the tumor to metastasize and spread elsewhere in the body.”
MIT and Harvard University researchers have now mapped out an additional layer of control that guides this cellular evolution—an array of structural changes to “chromatin,” the mix of proteins, DNA and RNA that makes up cells’ chromosomes. In a study of mouse lung tumors, the researchers identified 11 chromatin states—also called epigenomic states—that cancer cells can pass through as they become more aggressive.
“This work provides one of the first examples of using single-cell epigenomic data to comprehensively characterize genes that regulate tumor evolution in cancer,” says Lindsay LaFave, an MIT postdoc and the lead author of the study.
In addition, the researchers showed that a key molecule they found in the more aggressive tumor cell states is also linked to more advanced forms of lung cancer in humans, and could be used as a biomarker to predict patient outcomes.
Dr. Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research, and Dr. Jason Buenrostro, an assistant professor of stem cell and regenerative biology at Harvard University, are the senior authors of the study, which appeared in Cancer Cell.
Using a new technology for single-cell epigenome analysis that Buenrostro had previously developed, the team analyzed the epigenomic changes that occur as tumor cells evolve from early stages to later, more aggressive stages. They also examined tumor cells that had metastasized beyond the lungs.
This analysis revealed 11 different chromatin states, based on the locations of epigenomic alterations and density of the chromatin. Within a single tumor, there could be cells from all 11 of the states, suggesting that cancer cells can follow different evolutionary pathways.
As the structure of tumor cells’ chromatin changed, transcription factors tended to target genes that would help the cells to lose their original identity as lung cells and become less differentiated. Eventually many of the cells also gained the ability to leave their original locations and seed new tumors.
Much of this process was controlled by a transcription factor called RUNX2. In more aggressive cancer cells, RUNX2 promotes the transcription of genes for proteins that are secreted by cells. These proteins help remodel the environment surrounding the tumor to make it easier for cancer cells to escape.
The researchers also found that these aggressive, premetastatic tumor cells were very similar to tumor cells that had already metastasized.
“That suggests that when these cells were in the primary tumor, they actually changed their chromatin state to look like a metastatic cell before they migrated out into the environment,” LaFave said. “We believe they undergo an epigenetic change in the primary tumor that allows them to become migratory and then seed in a distal location like the lymph nodes or the liver.”
Spatial relationships of cells in the tumor microenvironment
Akoya Biosciences Inc. recently announced the application of the CODEX platform to a recent Cell publication titled “Coordinated Cellular Neighborhoods Orchestrate Antitumoral Immunity at the Colorectal Cancer Invasive Front.”
In what they are calling “a seminal approach to studying the spatial biology of colorectal cancer,” the authors established an analytical framework to analyze highly multiplexed imaging data and, in doing so, discovered unique spatial relationships between “neighborhoods” of cells in the tumor microenvironment.
Understanding the interactions between these cellular aggregates and their impact on antitumor immunity could advance our understanding of tumor progression and immunotherapy response, they say.
The research team at Stanford University and the University of Bern used the CODEX system for deep profiling of formalin-fixed paraffin-embedded tissues from 35 advanced-stage colorectal cancer patients with more than 50 protein markers simultaneously, at single cell resolution. As a result, the team discovered nine distinct cellular neighborhoods, each uniquely composed of certain immune and cancer cell types. These cellular neighborhoods were found to interact with one another in a manner that correlated with disease progression and prognosis.
Most recent studies have focused on the network of interactions between different cell types and their spatial context. This study, however, places an emphasis on analyzing tissue biology at two different levels, the interacting cell types as well as the tissue regions within which they are organized.
“The results from our study contribute to the growing body of biological knowledge needed to improve the development of immunotherapies,” said Dr. Garry Nolan, the Rachford and Carlota A. Harris Professor in the Department of Microbiology and Immunology at Stanford University School of Medicine. “Using CODEX technology for highly multiplexed imaging to study cell aggregates in situ and their impact on disease pathology and progression, we were able to gain valuable insights about how tumors can disrupt immune functionality and how antitumoral immunity requires organized, spatially-nuanced interactions between cellular neighborhoods in the tumor microenvironment. The results point to potential diagnostics and new targets for therapeutic intervention.”
How a complex enzyme protects cells from DNA damage
Scientists in the Mount Sinai Health System have used high-powered microscopy of molecules frozen at cryogenic temperatures to uncover, as they say, “for the first time how an enzyme called DNA polymerase zeta (Pol zeta) allows cells to fight against daily DNA-damaging events like ultraviolet light and industrial carcinogens” and to create a three-dimensional model of the complex enzyme.
The importance of these findings—published in Nature Structural & Molecular Biology—may provide insight for the development of drugs designed to inhibit DNA polymerase, particularly in oncology R&D around non-small-cell lung, prostate, and ovarian cancers, which often become resistant to chemotherapy after early use in patients.
The reason for that resistance is that chemotherapies like cisplatin actually depend on their DNA-damaging effects, so blocking or inhibiting the function of polymerase zeta makes the cancerous cells more sensitive to the therapeutic impact of chemotherapy.
“Resolving the structure of the complete Pol zeta enzyme at near-atomic resolution allows us to address long-standing questions of how this unique polymerase replicates through daily DNA-damaging events, while also providing a template for designing drugs against cancers that are refractory to conventional chemotherapeutics,” said lead author Dr. Aneel Aggarwal, a professor of pharmacological sciences at the Icahn School of Medicine at Mount Sinai.
The Mount Sinai team learned how the enzyme protects the cells from natural and manmade environmental as well cellular stresses through an intricate structure of four different proteins that connect to each other in a pentameric, or daisy chain-like, configuration.
“The development of effective inhibitors has been hampered in the past by a lack of structural information on Pol zeta,” explaines Aggarwal. “Our work now offers a much clearer picture, and we expect these new insights will spur efforts by scientists around the world to create effective new therapies. For the thousands of patients with tumors that are resistant to chemotherapy, these findings could prove to be particularly valuable by meeting an unfulfilled need in their battle against cancer.”
The lack of progress over the years was largely due to the fact that structural studies of DNA polymerase zeta were limited by the low yields and unattainability of well-diffracting crystals. Aggarwal and his team overcame that problem by employing cryo-electron microscopy. This technology, which allows for the imaging of rapidly frozen molecules in solution, is revolutionizing the entire field of structural biology through its high-resolution pictures of complex molecules.
Trans-Atlantic scientific partnership to tackle cancer’s toughest problems
Cancer Research UK and the National Cancer Institute (NCI) recently announced that they are the founding partners of the Cancer Grand Challenges initiative, which will target the growing global cancer burden by addressing critical roadblocks in research.
This new partnership brings the Cancer Grand Challenges investment to £426 million ($550 million). Cancer Research UK and NCI expect to co-fund approximately four awards for each round of Cancer Grand Challenges, with each multidisciplinary team being awarded approximately £20 million ($25 million) over five years, reportedly one of the largest awards in the world for cancer research.
Cancer Grand Challenges is a unique international platform, the partners says, marking a significant “gear shift” in efforts to confront the ever-growing global cancer burden. Cancer Research UK and NCI aim to encourage the research community across the globe to think creatively and to act more boldly than ever before to radically speed up progress against cancer.
“Having worked much of my life carrying out research related to cancer, I have seen the great progress we’ve made, but there is still a mountain of work left to do.” said Nobel Laureate Sir Paul Nurse, chair of the Cancer Grand Challenges Scientific Committee. “We need to take our understanding of cancer up a gear. Cancer Grand Challenges will allow the global research community to work in synergy together to make the advances that patients around the world need.”
The Cancer Grand Challenges is intended to be a platform to bring together governments, philanthropists, foundations and charities to take on the huge challenge of cancer.
Cancer Grand Challenges is an evolution of Cancer Research UK’s Grand Challenge initiative, through which seven teams have already been funded since 2017. Teams are tackling a range of challenges, which includes building 3D tumors that can be explored through virtual reality, allowing multiple doctors and scientists to look at the tumor at the same time so they can diagnose and treat patients better.
Another team is addressing the challenge of improving cancer treatment responses by manipulating the trillions of microbes found in the microbiome. The team have recently uncovered a link between E.coli and bowel cancer, a connection which has never been made before.
DNA changes in healthy bladder provide clues on how cancer arises
In what is said to be the first comprehensive study of DNA changes in healthy and diseased human bladder tissue, researchers have revealed that cancer-driving mutations are common in healthy bladder tissue. The study was conducted by scientists at the Wellcome Sanger Institute, the University of Cambridge and their collaborators.
The research uncovered high variation in the number and types of changes between individuals, indicating that a wide range of factors influence how bladder cancer develops. The researchers also provided new insights into the link between smoking and bladder cancer, whereby bladder tissue is exposed to tobacco chemicals present in urine.
Technological developments have enabled the detection of somatic mutations linked to cancer in normal tissues, providing insights into the earliest stages of cancer and raising the prospect of early detection and treatment strategies. This new study used DNA sequencing to better understand the genetic changes in healthy and diseased bladder tissue. Clinicians from the University of Cambridge provided donated bladder tissue from five people with bladder cancer and 15 people with no history of cancer.
Researchers at the Wellcome Sanger Institute then took 2,097 biopsies from the tissue samples, using a technique called laser-capture microscopy to isolate segments of just a few hundred cells. DNA from these samples was genome sequenced and the sequences were analyzed to characterize the landscape of somatic mutations.
The team found an unexpectedly high variability in the number and types of mutations and in the frequency of cancer-driving mutations between individuals, suggesting that a wide range of factors affect the accumulation of mutations in the bladder. Some of these factors could be identified by their “mutational signature,” or tell-tale patterns of mutation in the genome caused by a certain chemical or process.
Among other things, the study identified a new mutational signature associated with smoking, shedding light on why tobacco is the single greatest risk associated with bladder cancer. Though the bladder does not come into contact with smoke directly, the chemicals in tobacco products are filtered out of the body by the kidneys and come into contact with the bladder in the urine.
“One of the questions we sought to answer with this study was why bladder cancers have some of the highest mutation rates and cancer-driving mutations of any cancer type, even though the cells in the bladder divide slowly, reducing the chance of a genetic error,” said Dr. Andrew Lawson, first author of the study from the Wellcome Sanger Institute. “The high patient-to-patient variation in which genes were mutated and in the types of mutations may be consistent with the wide variety of factors that can contribute to bladder cancer. Further studies on the causes behind this variation could help uncover hidden causes of bladder cancer.”
The researchers were surprised to find that mutations in key cancer genes such as TP53, FGFR3 and TERT were largely absent from healthy bladder tissue, despite the high number of mutations overall. As mutations in these genes are common in bladder tumors, their presence is a strong indicator that disease has set in.
“Like many cancers, early diagnosis of bladder cancer gives the patient a much greater chance of survival. The presence of mutations in key cancer genes in bladder tumors that are usually absent in normal tissue opens up the possibility of looking for these changes in fragments of DNA that are present in urine,” noted Dr. Thomas Mitchell, a senior author of the study from Cambridge University Hospitals and the Wellcome Sanger Institute. “These ‘liquid biopsies’ could be a non-invasive way to screen for bladder cancer earlier, which could help reduce the number of people who die from this disease.”
Concluded Dr. Inigo Martincorena, lead author of the study from the Wellcome Sanger Institute: “This study reveals an unexpectedly rich landscape of mutation and selection in normal bladder, with large differences across individuals driven to some extent by our daily exposures. Thanks to technical advances, our understanding of how our cells mutate, compete and evolve as we age have been transformed over the last few years. In addition to shedding light on the origins of cancer and informing early detection efforts, these observations raise questions about the possible role of these widespread mutations in ageing and other diseases.”
Unleashing the immune system’s ‘STING’ against cancer
Scientists at Scripps Research have discovered a molecule that can activate a natural immune-boosting protein called STING. The findings mark a key advance in the field of oncology, as the STING protein is known for its strong antitumor properties.
STING (short for STimulator of INterferon Genes) marshals the immune system against viral and cancerous invaders and, because of its role in promoting antitumor immunity, has garnered enthusiastic interest from drug developers.
However, STING’s natural activators in the body are unstable DNA-related molecules that do not last long in the bloodstream. That has hindered the development of treatments based on them, and has prompted a search for a hardier STING-activating small molecule—one that can circulate in the blood and work against tumors systemically, wherever they may exist in the body.
The Scripps Research scientists, who reported their finding in Science, screened a set of suitable small molecules with diverse structures and identified several that activate STING. After modifying one of these molecules to optimize its properties, they found that delivering it systemically into mice with an injection greatly reduced the growth of an aggressive form of melanoma.
The discovery raises the possibility of a circulating drug that could activate STING and suppress a wide range of cancers.
“A systemic STING-activating molecule could have considerable utility, and not only as a therapeutic for cancer and infectious disease, but also as a probe for studying STING-dependent antitumor immunity and a host of other STING-related biological processes,” saids co-senior author Dr. Luke Lairson, an associate professor in the Department of Chemistry at Scripps Research.
Lairson and colleagues found that their optimized STING-activator, which they named SR-717, appears to activate the STING protein in the same way as its natural activators in the body. Using X-ray crystallography to image the interaction at atomic scale, they showed that both SR-717 and a known natural activator bind to the same site on STING and induce the same shape-change in the protein.
In an animal model of aggressive melanoma, SR-717 dramatically suppressed tumor growth, prevented metastasis, induced the presentation of tumor molecules to the immune system and robustly boosted levels around tumors of CD8+ T cells and NK cells—both of which are known to be among the immune system’s heaviest antitumor weapons. At this effective dose, there was no evidence of significant adverse side effects on the animals.
