High-resolution molecular atlas of a lung tumor in 3D

Pentimalli, T. M.; Schallenberg, S.; Leon-Perinan, D.; Legnini, I.; Theurillat, I.; Thomas, G.; Boltengagen, A.; Fritzsche, S.; Nimo, J.; Ruff, L.; Dernbach, G.; Jurmeister, P.; Murphy, S.; Gregory, M.; Liang, Y.; Cordenonsi, M.; Piccolo, S.; Coscia, F.; Woehler, A.; Karaiskos, N.; Klauschen, F.; Rajewsky, N.

doi:10.1101/2023.05.10.539644

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bioRxiv · 10.1101/2023.05.10.539644

High-resolution molecular atlas of a lung tumor in 3D

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Abstract

Cells live and interact in three-dimensional (3D) cellular neighborhoods. However, histology and spatial omics methods mostly focus on 2D tissue sections. Here we present a 3D spatial atlas of a routine clinical sample, an aggressive human lung carcinoma, by combining in situ quantification of 960 cancer-related genes across [~]340,000 cells with measurements of tissue-mechanical components. 3D cellular neighborhoods subdivided the tumor microenvironment into tumor, stromal, and immune multicellular niches. Interestingly, pseudotime analysis suggested that pro-invasive epithelial-to-mesenchymal transition (EMT), detected in stroma-infiltrating tumor cells, already occurred in one region at the tumor surface. There, myofibroblasts and macrophages specifically co-localized with pre-invasive tumor cells and their multicellular molecular signature identified patients with shorter survival. Moreover, cytotoxic T-cells did not infiltrate this niche but colocalized with inhibitory dendritic and regulatory T cells. Importantly, systematic scoring of cell-cell interactions in 3D neighborhoods highlighted niche-specific signaling networks accompanying tumor invasion and immune escape. Compared to 2D, 3D neighborhoods improved the characterization of immune niches by identifying dendritic niches, capturing the 3D extension of T-cell niches and boosting the quantification of niche-specific cell-cell interactions, including druggable immune checkpoints. We believe that 3D communication analyses can improve the design of clinical studies investigating personalized, combination immuno-oncology therapies.

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Pentimalli, T. M., Schallenberg, S., Leon-Perinan, D., Legnini, I., Theurillat, I., Thomas, G., Boltengagen, A., Fritzsche, S., Nimo, J., Ruff, L., Dernbach, G., Jurmeister, P., Murphy, S., Gregory, M., Liang, Y., Cordenonsi, M., Piccolo, S., Coscia, F., Woehler, A., Karaiskos, N., Klauschen, F., Rajewsky, N.. 2023-05-10. High-resolution molecular atlas of a lung tumor in 3D. https://doi.org/10.1101/2023.05.10.539644

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