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Cellular communication relies on the intricate interplay of signaling molecules, forming the Cell-cell Interaction network (CCI) that coordinates tissue behavior. Researchers have shown the capability of shallow neural networks in reconstructing CCI, given molecules' abundance in the Spatial Transcriptomics (ST) data. When encountering situations such as sparse connections in CCI and excessive noise, the susceptibility of shallow networks to these factors significantly impacts the accuracy of CCI reconstruction, resulting in subpar results. To reconstruct a more comprehensive and accurate CCI, we propose a novel method named Triple-Enhancement based Graph Neural Network (TENET). In TENET, three progressive enhancement mechanisms build upon each other, creating a cumulative effect. This approach can ensure the ability to capture valuable features in limited data and amplify the noise signal to facilitate the denoising effect. Additionally, the whole architecture guides the decoding reconstruction phase with integrated knowledge, which leverages the accumulated insights from each stage of enhancement to ensure a refined and comprehensive CCI reconstruction. The presented TENET has been implemented and tested on both real and synthetic ST datasets. Averagely, the CCI reconstruction using TENET achieves a 9.61% improvement in Average Precision (AP) and a 7.32% improvement in Area Under the Receiver Operating Characteristic (AUROC) compared to the existing state-of-the-art (SOTA) method. The source code and data are available at https://github.com/Yujian-Lee/TENET.

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Determining the prognostic association of different immune cell types in the tumor microenvironment is critical for understanding cancer biology and developing new therapeutic strategies. However, this is challenging in certain cancer types, where the abundance of different immune subsets is highly correlated. In this study, we develop a computational method named TimiGP to overcome this challenge. Based on bulk gene expression and survival data, TimiGP infers cell-cell interactions that reveal the association between immune cell relative abundance and prognosis. As demonstrated in metastatic melanoma, TimiGP prioritizes immune cells critical in prognosis based on the identified cell-cell interactions. Highly consistent results are obtained by TimiGP when applied to seven independent melanoma datasets and when different cell-type marker sets are used as inputs. Additionally, TimiGP can leverage single-cell RNA sequencing data to delineate the tumor immune microenvironment at high resolutions across a wide range of cancer types.

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In this Forum, we highlight how cutting-edge, proximity-dependent, enzymatic labeling tools, aided by sequencing technology developments, have enabled the extraction of spatial information of proteomes, transcriptomes, genome organization, and cellular networks. We also discuss the potential applications of proximity labeling in the unexplored field of spatial biology in live systems.

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A recent study on the immunotherapy treatment of renal cell carcinoma reveals better outcomes in obese patients compared to lean subjects. This enigmatic contradiction has been explained, in the context of the debated obesity paradox, as the effect produced by the cell-cell interaction network on the tumor microenvironment during the immune response. To better understand this hypothesis, we provide a computational framework for the in silico study of the tumor behavior. The starting model of the tumor, based on the cell-cell interaction network, has been described as a multiagent system, whose simulation generates the hypothesized effects on the tumor microenvironment. The medical needs in the immunotherapy design meet the capabilities of a multiagent simulator to reproduce the dynamics of the cell-cell interaction network, meaning a reaction to environmental changes introduced through the experimental data.