Biology subjects

Huyghe, M.

Publications and source records attributed to Huyghe, M..

5 recordsLinked to original sources

bioRxiv2025

Genetic barcoding of individual cells links cancer evolutionary trajectories and prognostic outcomes

Intratumoural heterogeneity (ITH) reflects cancer progression, by integrating clonal dynamics, cell plasticity, and metastatic potential of malignant cells. Defining the origins and evolutionary trajectories of tumour cells is central to preventing tumour growth and dissemination, yet significant gaps in knowledge persist. Here, we used an original single cell resolution lineage tracing system to investigate how ITH underlies changes in tumour cell states, such as the acquisition of an epithelial-to-mesenchymal transition (EMT) phenotype and invasive capacity. By combining in vivo genetic barcoding with single-cell transcriptomics, we uncover two parallel evolutionary trajectories toward EMT: one associated with alveolar differentiation, and another characterized by gene regulatory programs activated during stress and tissue regeneration. Of interest, only the gene modules defining the regenerative trajectory were found to correlate with poor survival in breast cancer patients. Our results also provide a quantitative framework to measure cellular plasticity that enables the identification of highly plastic cells and their gene signatures, correlating with rapid changes in transcriptional state, EMT features and aggressive cancer. These findings deliver a comprehensive view of in vivo clonal evolution in breast cancer, uncovering the interplay between lineage plasticity and tumour progression with quantitative and robust statistical approaches.

cancer biology↗

bioRxiv2025

Single-cell transcriptomics uncover conserved molecular mechanisms and functional diversification in multilayered epithelia

Multilayered epithelia, including skin, cervix, thymus, and prostate, arise from all three germ layers and perform diverse physiological functions, yet share a conserved layered architecture in which a supportive basal layer underlies differentiated suprabasal cells. To determine whether this common organization reflects a shared genetic program or tissue-specific regulation, we assembled a comprehensive single-cell atlas of 14 murine Multilayered epithelia. We identified a conserved p63-Notch axis that universally governs basal cell identity maintenance and suprabasal commitment. The p63-centered transcriptional program is shared, while Notch signaling recruits context-specific transcriptional modules to generate functional diversity. The layered architecture of epithelia spatially and temporally decouples conserved basal from context-specific suprabasal networks, compartmentalizing functional innovation across multilayered epithelia. Comparative genomics traces the p63-Notch axis to the root of vertebrates over 500 million years ago, showing that it was repeatedly co-opted through the incorporation of newly evolved genes in the suprabasal domain to generate novel epithelial functions. Our work establishes that evolution of multilayered epithelia operates through modular, compartmentalized diversification of a conserved scaffold, providing a unifying principle for how complex tissues achieve functional innovation while preserving structural integrity.

cell biology↗

bioRxiv2024

Conserved signals orchestrate self-organization and symmetry breaking of bi-layered epithelia during development and regeneration

Organ development relies on complex molecular mechanisms that guide initially homogeneous populations of stem cells to differentiate into specialized cell types within defined spatial patterns. While stable during homeostasis, the proper spatial organization of cell types must be re-established in case of tissue injury for successful regeneration of organ shape and function. How cells commit to a differentiation path is a central question in stem cell research; however, the coordination between tissue geometry and cell fate specification remains enigmatic. To elucidate the molecular mechanisms instructing self-organization and symmetry breaking of epithelial stem cells, we developed a multi-faceted approach combining in vitro organoids, ex vivo embryonic tissue explants, and single-cell quantitative imaging to investigate the dynamic acquisition of cell fate in four bi-layered epithelia, during embryonic development but also in regeneration. Our findings indicate that tissue architecture is the primary determinant of cell fate decisions in these tissues. Upon the initial cell internalization event, the homogeneous population of stem cell break symmetry. Through genetic and pharmacological perturbations, we have demonstrated that a tightly coordinated interplay between Hippo/YAP and Notch signaling is essential for conveying information from tissue architecture to functional cell differentiation and stem cell potency restriction. Globally, this study uncovers the inherent capacity of stem cells to self-organize into multicellular structures, where the precise position of each differentiated cell is critical to instruct their differentiation choices during embryonic development and regeneration.

developmental biology↗

bioRxiv2020

Paracrine interactions between epithelial cells promote colon cancer growth

Tumours are complex ecosystems composed of different types of cells that communicate and influence each other. While the critical role of stromal cells in affecting tumour growth is well established, the impact of mutant cancer cells on healthy surrounding tissues remains poorly defined. Here, we uncovered a paracrine mechanism by which intestinal cancer cells reactivate foetal and regenerative Yap-associated transcriptional programs in neighbouring wildtype epithelial cells, rendering them adapted to thrive in the tumour context. We identified the glycoprotein Thrombospondin-1 (THBS1) as the essential factor that mediates non-cell autonomous morphological and transcriptional responses. Importantly, Thbs1 is associated with bad prognosis in several human cancers. This study reveals the THBS1-YAP axis as the mechanistic link mediating paracrine interactions between epithelial cells in intestinal tumours.

cancer biology↗

bioRxiv2018

Lineage tracing of Notch1-expressing cells in intestinal tumours reveals a distinct population of cancer stem cells.

Colon tumours are hierarchically organized and contain multipotent self-renewing cells, called Cancer Stem Cells (CSCs). We have previously shown that the Notch1 receptor is expressed in Intestinal Stem Cells (ISCs); given the critical role played by Notch signalling in promoting intestinal tumourigenesis, we explored Notch1 expression in tumours. Combining lineage tracing in two tumour models with transcriptomic analyses, we found that Notch1 + tumour cells are undifferentiated, proliferative and capable of indefinite self-renewal and of generating a heterogeneous clonal progeny. Molecularly, the transcriptional signature of Notch1+ tumour cells highly correlates with ISCs, suggestive of their origin from normal crypt cells. Surprisingly, Notch1+ expression labels a subset of CSCs that show reduced levels of Lgr5, a reported CSCs marker. The existence of distinct stem cell populations within intestinal tumours highlights the necessity of better understanding their hierarchy and behaviour, to identify the correct cellular targets for therapy.

cancer biology↗