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Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
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Tumour evolution and microenvironment interactions in 2D and 3D space.

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Area of Science:

  • Cancer Biology and Spatial Omics

Background:

  • Understanding spatial interactions between cancer and non-cancer cells is crucial for deciphering tumor heterogeneity and evolution.
  • Tumor microenvironments are complex, with spatial organization influencing cancer progression and treatment response.

Purpose of the Study:

  • To investigate the spatial organization and cellular interactions within diverse tumor types using multi-omic spatial profiling.
  • To define and characterize tumor microregions and spatial subclones based on cellular composition and genetic alterations.
  • To explore the 3D spatial architecture of tumors and its relationship with immune cell infiltration and exhaustion.

Main Methods:

  • Visium spatial transcriptomics (ST) on 131 tumor sections across 6 cancer types.
  • Integration with single-nucleus RNA sequencing (snRNA-seq) and co-detection by indexing (CODEX) data.
  • 3D reconstruction using serial ST sections and application of deep learning for immune microenvironment analysis.

Main Results:

  • Defined 'tumor microregions' and 'spatial subclones' with distinct genetic alterations and oncogenic activities.
  • Identified spatial metabolic activity gradients and antigen presentation patterns within microregions.
  • Characterized variable immune cell infiltration, with T cells within microregions and macrophages at boundaries; identified immune hot/cold neighborhoods and immune exhaustion markers in 3D.

Conclusions:

  • Spatial organization and interactions within tumor microregions and subclones significantly impact tumor biology.
  • 3D tumor architecture influences immune cell distribution and immune evasion strategies.
  • This study provides a comprehensive framework for understanding spatial tumor evolution and microenvironment dynamics.