In the last few decades, scientists have uncovered numerous mechanisms of cancer cells to evade cellular checkpoints. Several findings in recent years have indicated that an upregulation of the protein FosB is a key mechanism for cancer metastasis and survival.
Yet, existing transcriptome studies of tumor cells fail to account for dynamic gene expression changes. Spatial transcriptomics, or spatial gene expression, is a new method that allows researchers to simultaneously study the gene expression of every single cell in a sample rather than the average expression of cells within each organ or tissue. In this way, spatial transcriptomics eliminates the need for averaging gene expression levels and enables researchers to capture unique aspects of biology. Here are 5 things spatial transcriptomics reveals about cancer cells.
1. Spatial Transcriptomics Reveals Cancer Invasion
Using spatial transcriptomics, researchers have discovered that cancer cells exhibit different gene expression profiles along the invasive front and within nontumorigenic tumors. The spatial differences in gene expression were present at a single cell level, while the average gene expression of tumor cells was not significantly different from non-tumorigenic cells. This indicates that genetic changes are more diverse than previously thought.
Spatial transcriptomics reveals the association between FosB and invasion. Higher levels of FosB correlated with faster tumor growth rates, higher invasiveness, and poor patient survival. Moreover, spatial transcriptomics indicates that the level of FosB was not uniform in the invasive front. Instead, it peaked at the tip of the invasive front. This provides proof that cell-to-cell variability is an important aspect of tumor aggressiveness.
The spatial transcriptomic approach also revealed a correlation between FosB and the levels of MMP2 in cancer cells. As expected, high levels of MMP2 correlated with invasive cell fronts and poor patient survival. Yet, quantitative spatial transcriptomics indicates that invasive cancer cells harbor high eukaryotic initiation factor 2 alpha (eIF2α) at their leading edge.
2. Spatial Transcriptomics Reveals Tumor Heterogeneity
Spatial transcriptomics has discovered that cancer cells at different stages of malignancy showed unique gene expression profiles in a single biopsy sample from patients. This heterogeneity was reflected in a wide range of genes, including cell surface receptors, adhesion molecules, and growth factors, which have been implicated in cancer progression.
The spatial transcriptomics data demonstrate that several genes highly expressed in cancer cells' tumorigenicity are not actively expressed at the invasive front. For example, high levels of MMP9 were found only within tumorigenic cells and not within the leading edge of invasive cancers. This suggests that the different stages of cancer are characterized by unique gene expression profiles and provides evidence for tumor cells with stem-like abilities in invasive cancers.
Spatial transcriptomics reveals that tumorigenic cells exhibited increased expression of several genes associated with metastasis. Cancer cells at the invasive front were also more motile than those residing within nontumorigenic tumors. Spatial transcriptomics also uncovers significant differences in gene regulation between invading and noninvasive cancer cells.
3. Spatial Transcriptomics Reveals the Dynamic Nature of Cancer Metabolism
The spatial transcriptomic data reveals the dynamic nature of cancer metabolism, with unique metabolite signatures for different stages of malignancy. The cells at the invasive front exhibited increased expression of several genes associated with oxidative phosphorylation, cellular respiration, and amino acid metabolism and decreased levels of glycolysis-associated genes. This suggests that cancer cells at the invasive front are metabolically more aggressive than those within nontumorigenic tumors.
Cancer cells within nontumorigenic tumors exhibited increased levels of several genes associated with ubiquitin-dependent proteolysis and autophagy. Besides being a metabolic process that degrades damaged proteins, it has also been implicated in the turnover of short-lived proteins, like transcription factors. This is particularly important for metastasis, where cancer cells must undergo extensive changes in gene expression to become motile and invasive.
4. Spatial Transcriptomics Reveals the Importance of Inducible Protein Synthesis and Epigenetic Regulation
Spatial transcriptomics reveals significant differences in protein synthesis between invasive cancer cells and those within nontumorigenic tumors. Cancer cells at the invasive front exhibited increased expression of several proteins required for inducible protein syntheses, such as phosphoinositide 3-kinase (PI3K) and P70 ribosomal S6 kinase (S6K) and proteins involved in chromatin remodeling.
On the other hand, invasive cancer cells showed decreased expression of p53, a protein essential for DNA repair and cell cycle arrest. Spatial transcriptomics also reveals that the invading cancers exhibited decreased expression of histone deacetylase (HDAC) and several lysine/arginine (K/R) methyltransferases. The hypomethylated chromatin profile of invasive cancers may explain why spatial transcriptomics detected decreased expression of FosB and its downstream targets in these tumor cells. This indicates that epigenetic regulation may be an important part of cancer progression since this dysregulation occurs even in the earliest stages of tumorigenicity.
Spatial transcriptomics uncovers marked differences in protein synthesis between invasive and noninvasive cancers. It also demonstrated that increased expression of several genes involved in ribosomal biogenesis, translation, and kinases occurred at the invasive front. Many of these proteins and kinases are regulated by p53, which was significantly downregulated. Spatial transcriptomics also reveals that many proteins involved in chromatin remodeling occurred at the invasive front. These proteins included several histone deacetylases and lysine methyltransferases.
5. Spatial Transcriptomics Reveals the Importance of Cell-Cell Communication
Spatial transcriptomics reveals that genetic differences between individual cancer cells could not explain spatial heterogeneity. Instead, it found that cell-to-cell variability was a key factor in determining tumor aggressiveness and tumor progression. For example, many soluble factors were highly expressed at the invasive front, including lymphotoxin beta receptor and macrophage migration inhibitory factor. These molecules have been linked to cancer progression.
Just as spatial transcriptomics detected important differences in gene expression between cells at different stages of malignancy, it also identified the importance of cell-cell signaling in cancer progression. Spatial transcriptomics found that the invasive front exhibited increased expression of several proteins associated with cell-to-cell communication, including c-Met and cAMP response element binding protein (CREB).
Spatial transcriptomics employs a unique methodology to analyze human and mouse tissue samples from patients with invasive cancer. This platform represents a major advance in cancer research and has revealed significant insights into the evolution of invasive cancers and how they relate to tumor progression.
Spatial transcriptomics has uncovered new information on how cancer cells change their gene expression as they transition from noninvasive tumors to invasive cancers. It also demonstrated that multiple factors could account for spatial heterogeneity within the same tumor, including differences in protein synthesis and cell-cell communication.
Conclusion
The spatial transcriptomics platform has yielded new insights into the evolution of cancer and increased our understanding of how cancer cells become more aggressive. Further studies are needed to investigate the role of cell-cell signaling in cancer progression and determine why some cancers exhibit stable invasive fronts while others have dynamic fronts. Reflection upon a decade of research in spatial transcriptomics and its impact on basic and translational research within the field of human health sciences would not be complete without recognizing a few milestones that were achieved during this time frame.
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