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| Item Type: | Preprint |
|---|---|
| Title: | High-resolution molecular atlas of a lung tumor in 3D |
| Creators: |
Pentimalli, T.M.  ORCID: https://orcid.org/0000-0002-8461-7918, Schallenberg, Simon, León-Periñán, D. ORCID: https://orcid.org/0000-0002-7970-0362, Legnini, I. ORCID: https://orcid.org/0000-0002-8984-5215, Theurillat, I. ORCID: https://orcid.org/0000-0002-1125-1951, Thomas, G., Boltengagen, A. ORCID: https://orcid.org/0000-0002-8356-9766, Fritzsche, S. ORCID: https://orcid.org/0000-0003-3335-3534, Nimo, J. ORCID: https://orcid.org/0000-0002-1565-7799, Ruff, L., Dernbach, G., Jurmeister, P., Murphy, S., Gregory, M., Liang, Y., Cordenonsi, M., Piccolo, S., Coscia, F. ORCID: https://orcid.org/0000-0002-2244-5081, Woehler, A. ORCID: https://orcid.org/0000-0001-5157-9313, Karaiskos, N. ORCID: https://orcid.org/0000-0001-7771-3947, Klauschen, F. and Rajewsky, N. ORCID: https://orcid.org/0000-0002-4785-4332
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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. |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2023.05.10.539644 |
| Date: | 10 May 2023 |
| Official Publication: | https://doi.org/10.1101/2023.05.10.539644 |
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