Biology subjects

Sempoux, C.

Publications and source records attributed to Sempoux, C..

4 recordsLinked to original sources

bioRxiv2024

Liver Sinusoidal Endothelial Cells and Laminin dictate cholangiocytes fate in chronic liver disease

In chronic liver disease (CLD), hepatocyte senescence limits conventional regeneration, prompting an alternative regeneration mechanism through transdifferentiation of reactive cholangiocytes (or ductular reaction cells - DRs). Yet, this alone is insufficient to avoid liver failure and transplantation, highlighting the importance of a deeper understanding of the mechanism. We focused on the DRs microenvironment. We identified laminin as a crucial component of the extracellular matrix to maintain DRs in a biliary phenotype, preventing their differentiation into hepatocytes. Liver sinusoidal endothelial cells (LSEC) are the cells regulating laminin degradation around DRs. By preventing LSEC capillarization during CLD, we enhanced DR differentiation into hepatocytes. We also demonstrated this causality in human samples. This is the first time that a mechanism for DR-driven regeneration has been described.

cell biology↗

bioRxiv2024

Spatial transcriptomics profiling of gallbladder adenocarcinoma: a detailed two-case study of progression from precursor lesions to cancer

BackgroundMost studies on tumour progression from precursor lesion toward gallbladder adenocarcinoma investigate lesions sampled from distinct patients, providing an overarching view of pathogenic cascades. Whether this reflects the tumourigenic process in individual patients remains insufficiently explored. Genomic and epigenomic studies suggest that a subset of gallbladder cancers originate from biliary intraepithelial neoplasia (BilIN) precursor lesions, whereas others form independently from BilINs. Spatial transcriptomic data supporting these conclusions are missing. Moreover, multiple areas with precursor or adenocarcinoma lesions can be detected within the same pathological sample. Yet, knowledge about intra-patient variability of such lesions is lacking. MethodsTo characterise the spatial transcriptomics of gallbladder cancer tumourigenesis in individual patients, we selected two patients with distinct cancer aetiology and whose samples simultaneously displayed multiple areas of normal epithelium, BilINs and adenocarcinoma. Using GeoMx digital spatial profiling, we characterised the whole transcriptome of a high number of regions of interest (ROIs) per sample in the two patients (24 and 32 ROIs respectively), with each ROI covering approximately 200 cells of normal epithelium, low-grade BilIN, high-grade BilIN or adenocarcinoma. Human gallbladder organoids and cell-ine derived tumours were used to investigate the tumour-promoting role of genes. ResultsSpatial transcriptomics revealed that each type of lesion displayed limited intra-patient transcriptomic variability. Our data further suggest that adenocarcinoma derived from high-grade BilIN in one patient and from low-grade BilIN in the other patient, with co-existing high-grade BilIN evolving via a distinct process in the latter case. The two patients displayed distinct sequences of signalling pathway activation during tumour progression, but Semaphorin 4A (SEMA4A) expression was repressed in both patients. Using human gallbladder-derived organoids and cell line-derived tumours, we provide evidence that repression of SEMA4A promotes pseudostratification of the epithelium and enhances cell migration and survival. ConclusionGallbladder adenocarcinoma can develop according to patient-specific processes, and limited intra-patient variability of precursor and cancer lesions was noticed. Our data suggest that repression of SEMA4A can promote tumour progression. They also highlight the need to gain gene expression data in addition to histological information to avoid understimating the risk of low-grade preneoplastic lesions.

cancer biology↗

bioRxiv2022

Tumor Microenvironment Cellular Crosstalk Predicts Response to Adoptive TIL Therapy in Melanoma

Adoptive cell therapy (ACT) using ex vivo expanded tumor-infiltrating T lymphocytes (TILs) can mediate responses in metastatic melanoma, but long-term efficacy remains limited to a fraction of patients. Here we interrogated tumor-microenvironment (TME) cellular states and interactions of longitudinal samples from 13 metastatic melanoma patients treated with TIL-ACT in our clinical study (NCT03475134). We performed single-cell RNA-seq and spatial proteomic analyses in pre- and post-ACT tumor tissues and showed that responders exhibited higher tumor cell-intrinsic immunogenicity. Also, endogenous CD8+ TILs and myeloid cells of responders were characterized by increased cytotoxicity, exhaustion and costimulation and type-I IFN signaling, respectively. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders have rich baseline intratumoral and stromal tumor-reactive T-cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study reveals CD8+ T-cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials. One-Sentence SummaryResponse to adoptive TIL therapy in melanoma is determined by CD8+ TIL-myeloid cell networks

immunology↗

bioRxiv2022

In vivo reprogramming leads to premature death due to hepatic and intestinal failure.

SUMMARYThe induction of cellular reprogramming by forced expression of the transcription factors OCT4, SOX2, KLF4, and C-MYC (OSKM) has been shown to allow the dedifferentiation of somatic cells and ameliorate age-associated phenotypes in multiple tissues and organs. Yet to date, the benefits of in vivo reprogramming are limited by the occurrence of detrimental side-effects. Here, using complementary genetic approaches, we demonstrated that continuous in vivo induction of the reprogramming factors leads to hepatic and intestinal dysfunction resulting in decreased body weight and premature death. By generating a novel transgenic reprogrammable mouse strain, which avoids OSKM expression in both liver and intestine, we drastically reduced the early lethality and adverse effects associated with in vivo reprogramming. This new reprogramming mouse allows safe and long-term continuous induction of OSKM and might enable a better understanding of in vivo reprogramming as well as maximize its potential effects on rejuvenation and regeneration.

molecular biology↗