Heterogeneity is a hallmark of cancer and perhaps one of the most important features associated with resistance to therapies and likelihood of recurrence and/or metastasis. Genomic instability contributes to genetic diversity, which leads to high levels of intratumoural heterogeneity. While genetic diversity is one contributor to phenotypic heterogeneity in tumors, the spatial variation in the tumor microenvironment (TME) also drives emergent phenotypic heterogeneity and intrinsic variation in resistance to drugs and the immune system. Ultimately, heterogeneity leads to higher likelihood of metastasis. Traditionally, pathology allowed for the assessment of heterogeneity. However, this was limited to gross assessment of the TME, through measurement of mitotic levels and severity of cancer invasion.
We present SimBioSys PhenoScope, a multi-scale analysis and visualization platform that integrates cancer data across scales to extract cross modality trends that drive cancer invasion. As a demonstrated use case for the platform, we present a vignette of using the platform to analyze pathology slides at three scales. Three convolutional neural networks (CNN) are developed and validated. The outputs of these networks were combined with 2D simulations of the metabolic behavior and growth of cells within the TME.
Two CNNs were developed and one implemented: one that identifies cells undergoing mitosis, one that segments individual cells and classifies their type, and one that segments five tissues from pathology slides. Additionally, transcriptional data was used to generate patient specific metabolic models. Each CNN was developed using training images and validated on the test images. The mitosis detection CNN was found to have an accuracy of 76.2% (precision=83%, recall=76%) in the test set. The classification CNN was found to have a Dice Similarity Coefficient (DSC) of 0.821 for segmenting cells and an F1 score for classifying cells ranging from 0.559 (F1i) to 0.756 (F1d). The segmentation CNN was found to have an accuracy of 78.1% with DSC ranging from 0.66 and 0.86 depending on tissue. The segmentations were input into a proprietary simulation framework along with patient-specific metabolic models to predict the spatial gradients of nutrients, and spatial organization of growth and metabolism. Simulations show multiple behaviors such as regions of high lactate production or consumption by cancer, and regions that differ by lactate production and alanine uptake in cancers. These behaviors were correlated with local cell mitoses and invasion of Tumor Infiltrating Lymphocytes.
Tools to examine cancers across scales and within the TME are currently lacking. We demonstrate a proof-of-principle approach of combining data across scales in a fashion that allows for novel predictions of TME behavior.
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