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Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis

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In silico tumor dissection pipeline for quantifying spatial diversity in the tumor ecosystem.

(A) Flow diagram depicting the overall study design. (B) Schematic of our pipeline for quantifying spatial diversity in pathological samples. H&E sections are morphologically classified and divided into regions to be spatially scored. The number of clusters k in the regional scores is indicative of the number of sub-populations of cell types in the tumor regions. (C) Examples of tumor regions with low and high diversity scores using the Shannon diversity index, accounting for cancer cells (outlined in green), lymphocytes (blue), and stromal cells (red). Cell classification is automated by image analysis. (D) The 3-D landscape of cell diversity scores on an example H&E section; the x- and y-axes are the geometric axes of the image, and the z-axis is cell diversity computed on a region-by-region basis. (E) The distribution of regional scores in a tumor from the METABRIC study with two regional clusters identified using Gaussian mixture clustering (grey shading: histogram; dashed black line: density; solid black lines: mixture components/clusters).

Fig 1

doi: https://doi.org/10.1371/journal.pmed.1001961.g001