Spatial biology is a rapidly growing field. It is important because cellular location and context matter when it comes to understanding disease progression, identifying biomarkers, developing therapeutics and monitoring therapeutic response. Recent research consistently shows that spatial mapping of the tissue architecture and cellular landscape can resolve correlated cell states and signaling networks that underlie organ function and pathology.
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Spatial biology is a field of study that explores how cells and molecules are distributed within and interact across a tissue. It involves investigation of the three-dimensional organization of biological systems, which highlights mechanisms and functions not captured, or fully understood, without their structural context. This is because tissue is highly heterogeneous, comprised of distinct cell types, often organized by conditions favorable for their survival.
In the case of oncology, solid tumors have dynamic ecosystems, containing malignant and non-malignant cell types – cancer cells, stromal cells and immune cells ― which change temporally and spatially depending on intrinsic and extrinsic mechanisms. Exploring cell phenotypes, correlated locations and cell-cell interactions in the tissue microenvironment can inform our understanding of biological processes and disease pathogenesis.
Generating spatial information from single cells is key to assessing or predicting cellular activity and determining the influence specific pathways may have in certain environments. Researchers can also use spatial biology techniques to study cell differentiation, immunosuppression in tumors, responses to new treatment options and many other applications that continue to improve patient outcomes.
Spatial omics technologies vary in spatial resolution, throughput capability and multiplexing capacity and have powered our knowledge of biology, with multiple methods being used to characterize tissues. See some of these techniques in more detail:
Traditional pathology methods such as immunohistochemistry are the gold standard in characterizing tissue morphology and confirming target molecule expression. When combined with genetic, RNA transcript and protein information, they can be used to decipher the molecular pathways that correlate to an observed phenotype.
Conventional bulk molecular biology techniques including RNA sequencing provide information on the overall RNA content or behavior of cell populations, but do not convey spatial information. These techniques can be more meaningful if spatial context is included with the data.
Instead of analyzing single cells in suspension, multiplex imaging technologies such as IMC™ result in high-dimensional analysis that can substantially broaden what can be discerned from one tissue sample. IMC reconstructs images from tissue sections scanned at single-cell resolution, with the specificity and high content of mass spectrometry.
Genomics, transcriptomics, proteomics and other omics approaches typically focus on generating data that will lead to specific knowledge about a particular question. Integration of the omics fields promotes a shift in strategy to support better understanding of biological systems as a whole and paves the way for advancement into areas such as precision medicine.
For example, cell state and behavior can be influenced by factors such as genetic aberrations contributing to tumor progression. Quantifying these factors to accurately measure the spatial location of genomic sequences together with phenotypic readouts enables analysis of distinct cell types and their copy number alterations. This type of multi-modal approach that combines spatial genomics with cell phenotyping provides a comprehensive way to identify factors contributing to gene expression changes in the tumor microenvironment.
Hartland Jackson, PhD, an investigator at the Lunenfeld-Tanenbaum Research Institute, Sinai Health, aims to better understand cancer at the single-cell level by investigating how the tumor microenvironment drives disease progression and therapeutic resistance. Before starting his own lab, Jackson worked with the team that pioneered high-plex single-cell analysis with IMC while completing his postdoc in the Bodenmiller Lab.
High-plex imaging by Imaging Mass Cytometry can assess more than 40 protein markers at once and can accommodate RNA markers for multi-omic analysis. Utilizing RNAscope™ to co-detect RNA in intact cells provides joint spatial transcriptomic and proteomic data and enables more comprehensive studies highlighting cell behavior in diseases including pancreatic cancer and metastatic melanoma.
With the ability to spatially resolve multiple proteins in a region of interest, IMC can support investigation of the relationships between genomic changes, transcript expression, cell phenotypes and tissue architecture. These investigations bridge omics data with location and behavior.
See poster about High-Plex Co-Detection of RNA and Protein to Explore Tumor-Immune Interactions Utilizing RNAscope With Imaging Mass Cytometry
Hear from Sara Wrobel, PhD, and Roberto Spada, PhD, about an accessible method for performing simultaneous co-detection of RNA and protein for multiplex imaging through a collaboration between Standard BioTools™ and Bio-Techne.
Read about an application of RNA and protein co-detection from imaging expert Daniel Schulz, PhD
An example of this combination of proteomics and gene expression data
Get a three-step workflow for IMC and RNAscope using 40-plus markers, 12 of which can be RNA.
Download technical note: Co-Detection of RNA and Protein to Explore Tumor-Immune Interactions Utilizing RNAscope With Imaging Mass Cytometry
Spatial biology can play an integral role in the progression from discovery through translational research and into the clinic. By identifying underlying mechanisms of cell behavior and responses to therapeutic interventions, spatial biology tools can be used to understand the implications of cell heterogeneity on patient outcomes.
From broad cellular landscape characterization to granular analysis of cell-cell interactions, IMC has been used to transform quantitative spatial data into knowledge to answer complex research questions. For example, IMC can help uncover biological signatures that may lead to the next generation of biomarkers important to diagnostic and therapeutic uses.
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Researchers and clinicians apply insights derived from IMC to the study of disease, drug development programs and precision medicine.
Tumor heterogeneity can limit the success of targeted therapies. The use of spatial biology to better understand the intricacies of these microenvironments helps identify how and why cancer progression occurs and what mechanisms can be targeted for response.
The complexity of the brain and nervous system has yet to be fully deciphered. Spatial context of neurons and other cells provides a better understanding of cell function and also allows a look into degenerative challenges and how they can begin to be addressed.
Determining immune system dysregulation using the spatial biology of immune cell activity and interaction improves our ability to detect and characterize autoimmune conditions and identify molecular signatures for effective immunomodulatory treatments.
Mapping the location of inflammatory markers and investigating how chronic inflammation can affect tissues is critical for developing effective interventions. Imaging can help detect and determine the extent of inflammation to understand disease development.
Visualization of the spatial distribution of pathogens and the host immune response reveals the dynamics of infection and what the immune system can and cannot do to combat it. This further provides the foundation for targeted therapies.
Spatial biology can address questions on disease pathogenesis, discovery of novel biomarkers and development of therapeutic approaches. Knowledge gained about triggers, pathways, consequences and treatments can then translate to clinical research.
Monitoring response to treatment and related clinical outcome is a key element of disease management. Spatial analysis enables the identification of reliable biomarkers for noninvasive response monitoring and the evaluation of pathological heterogeneity.
Early diagnosis and individually tailored treatments, or personalized medicine, aim to deliver the right treatment to the right patient at the right time. Imaging can help identify individuals suited for a particular intervention.
IMC facilitates the translation of spatial data to the clinic. Without challenges of autofluorescence, it is the trusted technology to generate images with precision and clarity.
How does IMC generate high-quality images?
High-dimensional spatial proteomics technologies utilize labeled antibodies to map the tissue microenvironment. Imaging Mass Cytometry (IMC) combines cytometry by time-of-flight (on which CyTOF® systems are based) with metal-tagged antibodies to generate spatial biology information. The technique uses a standard immunohistochemistry workflow.
Data analysis of the tissue or tumor microenvironment allows for the phenotyping and quantification of key cell types, the visualization of alterations in tissue architecture and the investigation of complex events at the cellular level. With a robust and reliable workflow, IMC allows for the quick generation of new insights into the pathophysiology of disease.
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40 slides. 40-plus markers. 24 hours.
Fast-forward spatial biology. New innovations in the IMC workflow make it possible for researchers to visualize 40-plus markers of the entire tissue in 20 minutes – taking spatial proteomics to new limits.
Imaging Mass Cytometry enables ultrafast multiplexed imaging using a unique one-step detection workflow. IMC technology images 40-plus markers simultaneously without time-consuming cyclic protocols or challenges of autofluorescence.
Spatial biology is the study of how individual cells fit within the context of a tissue, what their environment says about their behavior, where they are and why they are there. The term includes spatial transcriptomics, spatial genomics, spatial proteomics, spatial profiling and spatial omics. The significance of spatial biology in terms of life sciences and biomedical research is its power to expose how cellular interactions determine the tissue structure and spatial organization within the human body and those implications in disease pathogenesis.
Imaging Mass Cytometry (IMC) combines cytometry by time-of-flight with high-resolution laser ablation and metal-tagged antibodies to generate spatial biology information. Tissue sections are stained with panels of antibodies tagged with metal isotopes and scanned, generating plumes of the metal isotopes that are carried to a mass cytometer for simultaneous analysis. Sequential scanning of 1 µm spots yields a high-dimensional map of target proteins in a tissue or region of interest.
The Hyperion XTi™ Imaging System is powered by Imaging Mass Cytometry with a simple stain-image-analyze workflow, creating the ultimate platform for multiplex imaging. Hyperion™ XTi provides the fastest and most reliable tissue imaging workflow for clear and precise spatial analysis. Learn more about this system with a virtual demo.
The use of metal instead of fluorescent tags decreases crosstalk between channels, enabling high-content analysis in a single scan at subcellular resolution. Since IMC leverages time-of-flight mass spectrometry, it has the unique capability to simultaneously stain, acquire and analyze the markers of interest on a tissue section without interference from autofluorescent tissues or management of spectral overlap either in panel design or image analysis.
Histology and conventional pathology methods have been central in characterizing tissue morphology, which is then combined with genomic, transcriptomic and proteomic data to determine the molecular programming that correlates to an observed phenotype. Spatial biology techniques provide an in situ molecular characterization for a single-cell map of the complex tissue microenvironment.
Bulk analysis (such as RNA-seq) and single-cell analysis (such as flow cytometry or single-cell sequencing) provide information on either the overall RNA or protein content or behavior of single cells in a suspension. Combining this data with the spatial information of individual cells allows researchers to accurately assess the complex phenotypes and spatial interactions in the tissue microenvironment.
Single-cell analysis by IMC reveals cell phenotypes in context of a particular tissue providing insights into pathological processes. For example, using IMC to characterize cellular features, such as immune and stromal cells, of a tumor microenvironment could demonstrate clinical relevance by linking to prognosis.
Notably, IMC can be performed on paraffin-embedded tissue sections, allowing its application to the retrospective analysis of patient cohorts. Groups such as the Tumor Profiler (TuPro) Consortium, leading the Tumor Profiler Study, are helping push boundaries by taking an integrative approach to in-depth tumor profiling to support clinical decision making. With efforts to advance multi-omic data integration and improve data analysis solutions, the potential opportunity for IMC to impact personalized medicine is becoming increasingly clear.
Spatial profiling techniques enable the study of cell activity in the context of a tissue microenvironment. By classifying both the transcriptomic and proteomic signatures of a microenvironment, such as a tumor and the associated immune and stromal cells, spatial profiling facilitates evaluation of cell heterogeneity, details the evolution of a tumor and analyzes interactions between each tumor cell and its microenvironment. This provides the information required for correlating clinically relevant features in immuno-oncology, for example.
Innovations in imaging technologies allowing automation (emphasizing consistency, reproducibility and throughput), scalability (improvements on scan times and number of slides processed per day) and even 3D analysis generated from image sets, alongside the development of standardized biomarkers, are further pushing the boundaries of spatial biology into the clinic.
Learn more about the latest innovations in Imaging Mass Cytometry and the Hyperion XTi Imaging System with a virtual demo.
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