Taming brain tumour with spatially resolved transcriptomics

This is the Third Prize Winner of the 2023 Molecular Oncology Writing Competition: Uniting disciplines to tackle cancer.
Taming brain tumour with spatially resolved transcriptomics

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As part of World Cancer Day (4th Feb), the journal of Molecular Oncology invited researchers to take part in a writing competition aimed at highlighting how research in other areas of life sciences or technology influences the field of cancer biology and promotes cancer research. This entry, by Mitrajit Ghosh, received the third prize.

Glioblastoma (GBM) is the most common, aggressive and deadliest brain tumour that is incurable. Patients survive only for 15-16 months despite available multimodal therapies including neurosurgery, radiotherapy and chemotherapy. Therefore, there is an urgent need for newer and more effective therapy. The complex microenvironment of GBM is composed of heterogeneous cells, ineffective immune cells and aberrant blood vessels. The tumour cells exploit several other cells to grow, divide uncontrollably and survive by strategic immune evasion and drug resistance. For many years, researchers are trying to understand these interactions, to find what is going on and where. Without complete understanding of the reciprocal cell-cell interactions, devising a cure or therapy is impossible. Traditionally, immunohistochemistry has been used to study spatial architecture, however, it is limited to study a few genes at a time. In recent times, single cell technology has revolutionized the molecular profiling of tumours in an unprecedented manner. However, this type of technique needs tissue dissociation and cell segregation leading to loss of their spatial context. With the advent of spatial transcriptomics platform, now scientists can examine individual cells in detail as to where they are located and with whom they are interacting in the tumour.

Spatial transcriptomics as a powerful tool to probe cancer microenvironment

Spatial transcriptomics combine high-throughput imaging with sequencing technology to unravel intricate details about cell heterogeneity and interaction with the tumour. The Visium spatial transcriptomics platform from 10x Genomics makes use of spatially barcoded oligonucleotide microarrays for unbiased mapping of transcripts over tissue sections. This technique is increasingly popular to decipher the complexity in a tumour microenvironment as it overcomes the limitation of low throughput and complements single cell RNA sequencing to map rare and heterogenous cell types within tumour tissues. In 2020, the spatial transcriptomics method was also chosen for the “Method of the Year” award by Nature Methods, joining other powerful techniques like optogenetics, light sheet microscopy, organoids, and single cell transcriptomics.

Understanding brain tumour microenvironment and cellular crosstalk

The brain tumour microenvironment is characterised by several immune cells and stromal cells that interact with vasculature, extracellular matrix or other cells over time and they are spatially enriched in various parts of the tumour. The position, proximity and interaction of the cells are crucial for exploring therapeutic targets. Spatial transcriptomics when combined with multiplex immunohistochemistry and single cell sequencing can reveal a holistic view of tumour growth, spread and resistance. Several known genes can be located on the tissue and their location would determine their functionality in context to tumour. Even new or rare genes could be discovered on the spatial map to understand their regulation and crosstalk in shaping the tumour microenvironment.

Overcoming resistance to immunotherapy

With increase in cancer incidence worldwide, cell-based immunotherapy has come to the forefront as a promising solution to treat cancer. In this method, the host immune cells, mainly CD8+ T cells, being most popular so far, are genetically engineered or strategies for their effector functions are elevated to fight and eliminate cancer cells. However, GBM being one of the most aggressive solid tumours with complex microenvironments lead to failure of immunotherapy in clinical trials. This is because of the diverse cellular communication in GBM niche that can lead to immunosuppression or immune evasion. In order to overcome resistance to immunotherapy, spatial transcriptomics can help to locate cell interaction at tumour core vs tumour edge, identify cell heterogeneity and improve molecular subtyping of cancer.

We at the Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland, under guidance of Prof. Bozena Kaminska, as a part of recently granted PASIFIC project, are now therefore combining single cell sequencing, intravital imaging and spatial transcriptomics to understand role of genetic background on composition and functioning of immune cells in brain tumours.

Our research would integrate multi-omics technology and intravital imaging to define cellular and subcellular crosstalk in the tumour. Our work has potential to transform cancer research in an unprecedented way by deciphering spatial location of cells and their functions. Single cell analysis revolutionized understanding of single cell details in context to disease; however, a major limitation was that spatial context of the cell in the tissue was lost. Now combining spatial transcriptomics to single cell sequencing, the individual cell address within the tissue could be studied as how their interactions with neighbours are modulated in disease progression or how their proximity details changes or how their interaction responds to treatments. Thus, adding a new dimension to understanding cell communication in an indispensable manner. Current limitation of this technique is to attain cellular resolution at single cell scale and interpretation of data using bioinformatic tools. Standardization of these parameters would greatly enhance its capabilities as a powerful tool for studying complex tumour microenvironment.

Photo by Natalia Gusakova on Unsplash 

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