Biology subjects

Leon-Perinan, D.

Publications and source records attributed to Leon-Perinan, D..

5 recordsLinked to original sources

bioRxiv2025

Spatiotemporal dynamics of tumor microenvironment remodelling

During tumorigenesis, interactions between tumor and stromal cells progressively remodel the tumor microenvironment (TME) towards pro-tumoral functions. Understanding early TME remodeling dynamics is therefore crucial for developing interceptive therapies. However, clinical samples typically provide isolated, late tumorigenesis snapshots. To overcome this limitation, we generated triple-negative breast cancer mice that develop multifocal, asynchronous tumors along a continuous luminal-to-basal transdifferentiation trajectory. Ordering spatial transcriptomes from 100+ ducts along this trajectory reveals the spatiotemporal dynamics of TME remodeling and underlying molecular mechanisms. Cancer-associated myofibroblasts (myCAFs) emerge as key players in advanced tumors, where they orchestrate pro-invasive remodeling of the tumor-stromal interface. myCAFs are conserved in patient-derived xenograft models and steer tumor trajectories towards invasive phenotypes when co-injected with tumor cells in syngeneic mice. Our study shows that temporal ordering of spatially-resolved disease snapshots unravels some of the molecular "forces" that, starting from the cell-of-origin, propel cells/microenvironments along a disease trajectory.

cancer biology↗

bioRxiv2023

Open-ST: High-resolution spatial transcriptomics in 3D

Spatial transcriptomics (ST) methods have been developed to unlock molecular mechanisms underlying tissue development, homeostasis, or disease. However, there is a need for easy-to-use, high-resolution, cost-efficient, and 3D-scalable methods. Here, we report Open-ST, a sequencing-based, open-source experimental and computational resource to address these challenges and to study the molecular organization of tissues in 3D. In mouse brain, Open-ST captured transcripts at subcellular resolution and reconstructed cell types. In primary tumor and patient-matched healthy/metastatic lymph nodes, Open-ST captured the diversity of immune, stromal and tumor populations in space. Distinct cell states were organized around cell-cell communication hotspots in the tumor, but not the metastasis. Strikingly, the 3D reconstruction and multimodal analysis of the metastatic lymph node revealed spatially contiguous structures not visible in 2D and potential biomarkers precisely at the 3D tumor/lymph node boundary. We anticipate Open-ST to accelerate the identification of spatial molecular mechanisms in 2D and 3D.

systems biology↗

bioRxiv2023

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

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.

systems biology↗

bioRxiv2020

Metazoan-like kinetochore arrangement masked by the interphase RabI configuration

During cell cycle progression in metazoan, the kinetochore, the protein complex attached to centromeres which directly interacts with the spindle microtubules, the vehicle of chromosome segregation, is assembled at mitotic onset and disassembled during mitotic exit. This program is assumed to be absent in budding and fission yeast because kinetochore proteins are stably maintained at the centromeres throughout the entire cell cycle. In this work, we show that the assembly program at the mitotic onset of the Ndc80 complex, a crucial part of the outer kinetochore, is unexpectedly conserved in Schizosaccharomyces pombe. We have identified this behavior by removing the Rabl chromosome configuration during interphase, in which centromeres are permanently associated with the nuclear envelope beneath the spindle pole body. Hence, the Rabl configuration masks the presence of a program to recruit Ndc80 at mitotic onset in fission yeast, similar to that taking place in metazoan. Besides the evolutionary implications of our observations, we think that our work will help understand the molecular processes behind the kinetochore assembly program during mitotic entry using fission yeast as the model organism.

cell biology↗

bioRxiv2020

Identification of a meiosis-specific chromosome movement pattern induced by persistent DNA damage

As one of the main events occurring during meiotic prophase, the dynamics of meiotic chromosome movement is not yet well understood. Currently, although it is well-established that chromosome movement takes an important role during meiotic recombination promoting the pairing between homologous chromosomes and avoiding excessive chromosome associations, it is mostly unclear whether those movements follow a particular fixed pattern, or are stochastically distributed. Using Schizosaccharomyces pombe as a model organism, which exhibits dramatic meiotic nuclear oscillations, we have developed a computationally automatized statistical analysis of three-dimensional time-lapse fluorescence information in order to characterize nuclear trajectories and morphological patterns during meiotic prophase. This approach allowed us to identify a patterned oscillatory microvariation during the meiotic nuclear motion. Additionally, we showed evidence suggesting that this unexpected oscillatory motif might be due to the detection of persistent DNA damage during the nuclear movement, supporting how the nucleus also regulates its oscillations. Our computationally automatized tool will be useful for the identification of new patterns of nuclear oscillations during gametogenesis.

cell biology↗