Biology subjects

Le Marois, A.

Publications and source records attributed to Le Marois, A..

5 recordsLinked to original sources

bioRxiv2026

Intravital imaging uncovers remodelling of humanised bone marrow-like niches

The bone marrow haematopoietic niche is composed of a diverse array of cell types and extracellular matrix components that together support healthy haematopoiesis. However, live imaging of the bone marrow microenvironment is hampered by tissue accessibility limitations. Using intravital imaging through a titanium imaging window, we investigated the dynamics of human haematopoietic cells and mesenchymal stromal cells within an ectopically implanted humanised scaffold in an immunodeficient murine host. These cell populations expand and differentiate over time, accompanied by progressive remodelling of the scaffold. We observe migration of murine endothelial cells into the scaffold, leading to the formation of a vascular network during the initial development of the humanised niche. Subsequently, the dense collagen matrix that makes up the implanted niche is altered and larger gaps form in regions populated by mesenchymal stroma cells. Collectively, our findings demonstrate dynamic remodelling of the extracellular milieu that supports haematopoietic cell development and establish a platform for longitudinal, in vivo investigation of these processes. Altogether, we describe a novel model that aligns with the 3R guiding principles and enables real-time assessment of bone marrow cell dynamics in vivo. Summary statementRatcliffe and Mian et al. image in vivo dynamics of a bone marrow haematopoietic niche model.

cell biology↗

bioRxiv2025

Cell migration sculpts evolutionary dynamics favouring therapy resistance in lung cancer

The evolution of cancer undermines the long-term efficacy of therapy. In this study, we combine experimental, computational, and clinical data analysis to investigate factors influencing the competition of subclones in lung cancer. Lineage tracing reveals unexpected variation in the long-term fate of neutral subclones, with subclones arising near the edge of tumours being favoured. Low levels of cell migration and cell mixing lead to high cell densities in the interior of the tumour that suppress proliferation. Using agent-based modelling and in silico analysis we inferred the extent of cell mixing in human tumours from the TRACERx lung cancer study. This reveals correlations between Epithelial to Mesenchymal Transition (EMT), stromal fibroblasts and levels of cell mixing. Experimental analysis confirms that both TGF{beta}-driven EMT and stromal fibroblasts reduce the variability in subclone fate and promote subclone mixing. Moreover, mixing favours clonal sweeps by subclones resistant to therapy-induced cell killing. Together, these analyses demonstrate that EMT and stromal fibroblasts sculpt tumour evolution by promoting cell mixing and thereby favour the rapid dominance of therapy resistant subclones.

cancer biology↗

bioRxiv2025

Multimodal profiling unveils a reversible basal-like breast cancer cell state resistant to AKT inhibition

The PI3K/AKT/mTOR pathway is central to cell metabolism and growth. However, pharmacological inhibition of the pathway is not uniformly effective across cancer types, or even within a single cancer model. In this study, we leverage oblique plane microscopy of triple negative breast cancer organoids, as well as lineage tracing to uncover a source of heterogeneity. Non-genetic resistance to AKT inhibition is associated with basal cell features of normal breast epithelium and the master transcription factor of basal cell state, {Delta}Np63, is sufficient to confer resistance. Cells can transition between states within four weeks and therefore, AKT inhibition only delays tumour growth, with tumours rich in KRT14+ cells resulting. Thus, under selection, triple negative breast cancer exploits a repertoire of cell states inherent to the breast.

cancer biology↗

bioRxiv2025

AI4CellFate: Interpretable Early Cell Fate Prediction with Generative AI

Live-cell imaging provides a unique insight into complex cellular processes including single cell fate, but remains limited by both low-throughput and the lack of generalisable analytics for the multidimensional datasets it produces. This work introduces AI4CellFate, an interpretable and data-driven machine learning framework for predicting cell fate from microscopy timelapses, applied here to cancer therapy. By integrating generative AI and contrastive learning, AI4CellFate enables early fate prediction as well as visualisation of biologically relevant features, with limited annotation.

bioinformatics↗

bioRxiv2023

Oncogenic PIK3CA corrupts growth factor signaling specificity

Pathological activation of the PI3K/AKT pathway is among the most frequent defects in human cancer and is also the cause of rare overgrowth disorders. Yet, there is currently no systematic understanding of the quantitative flow of information within PI3K/AKT signaling and how it is perturbed by disease-causing mutations. Here, we develop scalable, single-cell approaches for systematic analyses of signal processing within the PI3K pathway, enabling precise calculations of its information transfer for different growth factors. Using genetically-engineered human cell models with allele dose-dependent expression of PIK3CAH1047R, we show that this oncogene is not a simple, constitutive pathway activator but a context-dependent modulator of extracellular signal transfer. PIK3CAH1047Rreduces information transmission downstream of IGF1 while selectively enhancing EGF-induced signaling and transcriptional responses. This leads to a gross reduction in signaling specificity, akin to "blurred" signal perception. The associated increase in signaling heterogeneity promotes phenotypic diversity in a human cervical cancer cell line model and in human induced pluripotent stem cells. Collectively, these findings and the accompanying methodological advances lay the foundations for a systematic mapping of the quantitative mechanisms of PI3K/AKT-dependent signal processing and phenotypic control in health and disease. One-sentence summarySingle-cell signaling and information theoretic analyses reveal that oncogenic PI3K/AKT activation leads to a gross reduction in signaling specificity, context-dependent EGF response amplification as well as increased phenotypic heterogeneity.

systems biology↗