Spatial Omics Spotlights the Players in the Tumor Microenvironment

GEN BiotechnologyVol. 2, No. 5 News Feature: Spatial OmicsFree AccessSpatial Omics Spotlights the Players in the Tumor MicroenvironmentSachin RawatSachin Rawat*Address correspondence to: Sachin Rawat, Freelance Science Writer. E-mail Address: [email protected]Freelance Science Writer.Search for more papers by this authorPublished Online:16 Oct 2023https://doi.org/10.1089/genbio.2023.29115.sroAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Researchers are using spatial omics to look deeper into the tumor microenvironment and unravel tumor heterogeneity with an eye on gleaning important clinical insights.Tumor immune microenvironment of human colorectal cancer. Cancer cells in green and immune cells in magenta. (Credit: NanoString Technologies)Many hard-to-treat cancers often recur months or years after successful treatment. “You could have one cell that escapes treatment and it's that one cell that will populate and be resistant and allow for a recurrence to happen,” said Jasmine Plummer, founding director of the Center for Spatial Omics at St. Jude Children's Research Hospital.Investigating such tumors with even single-cell omics technologies could miss these resistant cells. Before analysis, single-cell technologies destroy the cancer tissue to look at what's happening in the tissue as a whole. However, a lot of the interesting stuff inside tumors happens at the level of individual cells and depends on the context in which they exist. Single-cell technologies lose this spatial context when the cells are broken up.This is where spatial omics come in.With advances in omics technologies, cancer biologists have extensive information on the genes, proteins, and other metabolites that make up the messy environment of a tumor. Single-cell omics goes further, enabling the identification of all cell types in a tumor sample. This has only deepened our understanding of the extreme heterogeneity of tumor cells. Spatial omics technologies are placing these insights in the spatial context.Jasmine Plummer, Founding Director of the Center for Spatial Omics at St. Jude Children's Research HospitalTake gene expression, for example. Single-cell transcriptomics reveals which genes are being expressed across different cell types. But it doesn't say where these cells are in the tumor. Spatial transcriptomics technologies fill this gap by simultaneously recording spatial coordinates with gene expression data. This is the crux of the growing field of spatial omics: assigning pin codes to omics data.Spatial transcriptomics technologies such as in situ hybridization and in situ sequencing allow researchers to capture transcriptomes without losing spatial information. The former uses fluorescent, gene-specific probes that bind mRNAs, whereas the latter sequences the transcripts directly in a section of a fixed tissue.Complementing these imaging-based methods are other spatial technologies based on next-generation sequencing. These include high-definition spatial transcriptomics (HDST) and deterministic barcoding in tissue for spatial omics sequencing (DBiT-Seq). HDST uses spatially barcoded bead arrays to map RNA to location on histological sections. DBiT does the same for both proteins and RNA, enabling investigation of RNA-protein interactions with a spatial context. Technologies to study proteins and other metabolites are similar in principle to those developed to study transcripts. More recently, the push toward investigating multiple layers of information at once is driving the development of spatial multiomics tools like DBiT.The Diverse Tumor MicroenvironmentCancer cells must continuously evade the immune system while establishing the infrastructure to support their uncontrolled growth. That infrastructure requires careful communication with a diverse coterie. It includes healthy cells in the host tissue, immune cells that must be tricked, and blood vessels that the tumor needs to spread, among others. These make up a dynamic ecosystem known as the tumor microenvironment (TME)1 which plays a critical role in the growth and spread of a tumor.Charlotte Stadler, Co-director of the Spatial and Single Cell Biology platform (SSCB) and Head of the Spatial Proteomics Unit at SciLifeLabBy integrating single-cell omics and spatial omics, researchers finally have a way to create detailed maps of different tissues, including cancers. In an article published in Molecular Systems Biology, researchers created a single-cell atlas of the human liver TME.2 The researchers found recurring interactions between the carcinoma cells and stromal cells around them, suggesting that drugs that target these interactions could be more broadly applicable.In another study published in Cell, scientists showed that immune T cells exhibit a remarkable phenotypic diversity3 in the breast TME. Not only do they far outnumber the types of T cells in healthy breast tissues but also the activation states of the tumor T cell types are in a continuum. Further, the study suggested that the diversity of the immune cells was a consequence of the diversity of local microenvironments within the tumor.Tumors have a complicated immune ecology that helps them “become invisible to the immune system or tell the immune system to stop sniffing so it doesn't find it or tell the T cells not to try to kill tumor cells,” said Joseph Lehar, senior vice president of R&D strategy at Owkin, a French-American AI biotech startup.In tumor immune biology, the decisions made by cells about whether to kill cells suspected to be tumors are highly localized. “It's all about what a particular tumor cell or group of cells looks like and the immune cells are sensing that and then responding to it in a particular way,” Lehar added. A spatial understanding of the immune microenvironment of tumors is critical to be able to tackle untreatable cancers. This is because a tumor's ability to evade the immune system is central to both how it establishes the required architecture to grow and how it resists treatments.Another critical aspect of the TME is the presence of a hypoxic niche. A phenomenon that marks malignant tumors, this is a less-than-physiological level of oxygen that underlies the different cell signaling architecture within tumors. In a study published in Immunity, researchers showed that hypoxic niches attract and hide tumor immune cells.4 Combining spatial information with single-cell transcriptomics, they demonstrated that crosstalk between glioblastoma and immune cells in the hypoxic niche is crucial in suppressing the immune system.The TME also consists of additional mechanisms that shape the fate of a tumor by their interactions with both cancer and healthy cells. These include the extracellular matrix, free lipids, and mechanical cues, to name a few. To map these components along the tumor, researchers leverage other spatial profiling technologies, often used in conjunction with spatial omics, such as multiplexed imaging5 and mass cytometry.6In multiplexed imaging, “we use antibodies to detect a huge range of different proteins in the very same tissue section,” said Charlotte Stadler, codirector of the Spatial and Single Cell Biology platform and head of the spatial proteomics unit at the Swedish national research center, SciLifeLab (Fig. 1). This allows researchers to do “deep phenotyping and know what cell types are close in space and potentially interacting with one another.” Deep phenotyping, a term increasingly in focus in the precision medicine space, refers to phenotyping at multiple levels of omics data.FIG. 1. Researchers in Charlotte Stadler's group at SciLifeLab develop and use spatial proteomics methods for clinical applications in cancer.(Credit: Niklas Norberg Wirtén)Mass cytometry, similarly, allows researchers to track far more metabolites than conventional cytometry techniques. Such spatial profiling techniques are also critical to enable three-dimensional (3D) spatial omics. While maps of tumors obtained with spatial omics are often two dimensions (2D), tumors themselves exist in 3D. 3D spatial omics provide a complete picture of what's happening within tumors and, consequently, better insights.Tumors Are Highly HeterogeneousDifferent cells within a tumor have different genotypic and phenotypic makeup. Even in a genetically homozygous population of cancer cells within a tumor, the cells differ considerably phenotypically.7 Genomic instability, considered an important hallmark of tumor development, is the main driver of high cellular diversity in tumors.The high diversity of cells within a tumor “is pivotal for comprehending the multifaceted functions of tumor cells and their intricate relationship with the microenvironment,” said Dana Adel Mustafa, a cancer researcher at the Erasmus University Medical Center.By applying spatial omics techniques to cancer tissues, biologists are learning more about the heterogeneity of different tumors. Spatial omics technologies are rapidly advancing cancer research by producing hypothesis-generating data on tumor heterogeneity. For example, in a study published in Cancer Cell, researchers used spatial transcriptomics to investigate the heterogeneity in renal cell carcinoma. They observed that intratumoral heterogeneity far outweighs that of somatic mutations8 in kidney cancer.More specifically, the location of immune T cells in the tissue, rather than the mutations they have accumulated, primarily defines the level of their dysfunction. This study was part of the Human Cell Atlas consortium, a wider effort to create a comprehensive atlas of all the cells in a healthy body. Among other objectives, the Human Cell Atlas would serve as a benchmark to study how cancers differ from healthy tissues at the spatial level.Dana Mustafa, Assistant Professor at Erasmus University Medical CenterAlice Ly, Director of Spatial Biology Applications at Aspect AnalyticsThat tumors have high heterogeneity was already evident from standard imaging techniques. Spatial omics differ from previous work by “providing high-resolution molecular insights and shedding light on intricate biological interactions,” said Mustafa. In cancer treatment, this could be the difference that allows researchers to take on drug-resistant cancers.“You often need multiple omics modalities to see the true extent of the heterogeneity because each omics level, regardless of whether it is spatial or bulk or single cell, is only capturing a sub-fraction of the molecular heterogeneity within a cell,” said Alice Ly, director of Spatial Biology Applications at Aspect Analytics, a Belgian company that develops custom software solutions for spatial multiomics.Despite a plethora of choices, the most common omics technologies in spatially resolved studies of tumors are transcriptomics and proteomics. Spatial transcriptomics and spatial proteomics are complementary. “If you find interesting profiles from the transcriptomics, you would use spatial proteomics to see which particular cellular phenotype has this or that transcriptional profile,” said Stadler.As a growing field, spatial omics has yet to overcome many limitations. It is costly and requires diverse, technical expertise to bring together data from multiple high-throughput sequencing and imaging modalities. Analyzing this data is computationally expensive and time-consuming (files often run into hundreds of gigabytes). Furthermore, “while various pipelines and algorithmic programs have been developed to expedite and simplify data analysis, the interpretation of results remains a challenging and evolving facet,” explained Mustafa.From Spatial Omics to Clinical OutcomesSpatial omics describe the tumor landscape in extensive detail, but these insights need to translate into clinical outcomes to benefit cancer patients. Spatial omics are already generating clinically relevant insights. “Studies have shown that the immune system, the infiltration of different types of immune cells, has implications for how well a patient will respond to certain therapies,” said Stadler.One way that spatial omics could be applied to clinical oncology is to look at many proven clinical markers in a tissue section to determine the specific tumor subtype. “It could also be used to transfer interesting findings from next-generation sequencing data of relevant markers to see whether they have a significant prognostic value,” added Stadler.Despite its promises, computation remains a major bottleneck. Plummer stresses that integrating data from different technologies and analyzing them in a meaningful way is what's the field missing the most. “That is because the data sources are very large files and take days to run.”Companies such as Aspect Analytics, Owkin, and Aspect Analytics are working to change that with artificial intelligence. Aspect Analytics's technology enables multimodal investigation of tissue sections. The company has registration strategies to “overlay data sets from different modalities, different vendors, different technologies and so forth, to create a common coordinate framework to allow combined analysis of these data sets,” says Ly.Working with partners in industry and academia, Owkin is building MOSAIC, a spatial multiomics platform. By generating spatial omics data and analyzing it in combination with multimodal data of samples from thousands of patients using AI, it hopes to go further in understanding the molecular bases of different cancers.For instance, the platform could enable accurate diagnosis of many cancers with tricky diagnoses, such as triple-negative breast cancer (TNBC). TNBC gets its name from its lack of the three receptors commonly found in breast cancers, a condition that makes diagnosing it difficult. “When someone gets TNBC, what they really have is one of 20 diseases or so and no one knows what they are. Most of the drugs that you might try on them are going to be the ones that aren't going to fit their biology,” said Lehar.Regarding TNBC, Plummer said that “we have seen that even within those tumors that are age-matched and matched for TNBC, there are changes within the cell neighborhoods.” This presents a formidable challenge for MOSAIC and other spatial omics projects: to identify molecular subtypes of TNBC that reveal the different biologies happening for different patients.In the more immediate term, Plummer sees spatial omics to be applied more broadly at St. Jude's. Many patients come there following unsuccessful standard-of-care treatments for pediatric cancer at other medical institutes. Plummer suggested that those are the cases where spatial oncology could have its first wins. “We want to show effectively, if we have clinical trials, all the levels of information by which we've changed that tumor, and that tumor is now getting attacked and necrotic and going away.”Cancer biologists are excited about overlaying omics data over tissue images to generate multilayered pictures of a tumor. This allows them to produce a physical framework to map tumors in rich detail, learning about how differences along the spatial coordinates of a tumor shape its biology. As the field overcomes its technical limitations, it will open up clinical applications for both prognostics and treatment. By looking at tumors in rich 2D and 3D maps and at different stages, researchers will learn more about how tumors evolve in response to treatments.References1. Jin MZ, Jin WL. The updated landscape of tumor microenvironment and drug repurposing. 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Cancer Cell 2022;40(12):1583–1599; doi:10.1016/j.ccell.2022.11.001 Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Volume 2Issue 5Oct 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Sachin Rawat.Spatial Omics Spotlights the Players in the Tumor Microenvironment.GEN Biotechnology.Oct 2023.342-346.http://doi.org/10.1089/genbio.2023.29115.sroPublished in Volume: 2 Issue 5: October 16, 2023PDF download