Biology subjects

Lachaud, C.

Publications and source records attributed to Lachaud, C..

5 recordsLinked to original sources

bioRxiv2026

TERT drives liver tumorigenesis beyond telomere elongation

We generated two mouse models, p21/Tert and p21/TertCi, expressing either telomerase reverse transcriptase (TERT) or a catalytically inactive variant under the control of the p21 promoter. By 18-20 months of age, approximately 25% of mice from both genotypes developed liver tumors with histopathological features resembling human hepatocellular carcinoma (HCC). Whole-exome sequencing identified activating Ctnnb1 mutations and recurrent PP1 subunit alterations in p21/Tert tumors, whereas p21/TertCi tumors harbored activating HrasGln61Lys mutations associated with elevated C>A transversions. Both models exhibited chromosomal aberrations commonly observed in human HCC. Transcriptomic analyses revealed that {beta}-catenin-activated tumors recapitulated gene expression signatures of human HCC, while MAPK-mutated tumors showed profiles consistent with MAPK/ERK pathway activation. Metabolically, both genotypes demonstrated increased glycolysis and suppression of gluconeogenesis, including downregulation of FBP1, but expressed distinct NRF2 target genes. Spatial profiling further revealed reduced HNF4-positive hepatocytes across tumors, independent of Hnf4 transcription, and markedly diminished immune cell infiltration particularly in {beta}-catenin-activated tumors. Collectively, these findings uncover telomere-independent functions of TERT and identify molecular and metabolic features with potential relevance for predicting immunotherapy response.

cancer biology↗

bioRxiv2026

Single Spectral Flow Cytometry Panel for Simultaneous Detection of Hematopoietic Stem, Progenitor, and Mature Lineages in Mouse Bone Marrow

Hematopoiesis occurs in the bone marrow of adult mammals and is supported by hematopoietic stem cells that sustain lifelong blood cell production. Pathological conditions can disrupt HSC differentiation, causing anaemia, immunodeficiency, and other cytopenias. Therefore, precise and simultaneous identification of hematopoietic populations from stem to mature cells is essential for understanding disease mechanisms and developing targeted therapies. In order to study these alterations, flow cytometry is generally a need-to-have monitoring technique. However, most cytometry panels are designed to thoroughly study a particular population, leaving out potential discoveries on other populations from the same microenvironment. Here we present the design of complex 19-marker spectral flow cytometry panel capable of simultaneously identifying HSPCs, erythroid, myeloid and lymphoid cells within a single murine BM sample. This integrated approach replaces multiple conventional panels and enables comprehensive mapping of hematopoietic differentiation from a single assay. Validation confirmed accurate detection of long-term and short-term HSCs, multipotent progenitors, common myeloid and lymphoid progenitors, and erythroid populations from proerythroblasts to reticulocytes. UMAP visualization captured the continuous trajectory of differentiation. We validated our method on aged and {beta}-thalassemic mouse models showing a clear detection of hematopoiesis and erythropoiesis alterations respectively. This panel provides a robust, flexible, and scalable platform suitable for both basic research and translational studies.

physiology↗

bioRxiv2025

Non-canonical TERT function mitigates adipose tissue inflammation in obesity by modulating stem cell-macrophage communication and macrophage states

Background and aimsObesity drives adipose tissue (AT) expansion and chronic inflammation, leading to metabolic dysfunction through adipocyte hypertrophy, impaired ASPC differentiation, immune infiltration, and fibrosis. Stromal vascular remodeling prominently features expansion of Gdf15- and Trem2-expressing lipid-associated macrophages (LAMs), which respond to adipocyte stress and act as lipid scavengers to buffer excess lipids released by adipocytes. Here, we examined macrophage reprogramming in p21+/Tert and p21+/TertCi mice, which express active TERT or its catalytically inactive TERTCi mutant from the endogenous Cdkn1a promoter. ResultsFollowing HFD exposure, conditional expression of TERT or TERTCi resulted in a pronounced downregulation of p21 in macrophage subsets, accompanied by a reduction in AT inflammation. Notably, TERT and TERTCi expression reshaped the adipose-tissue macrophage (ATM) landscape depleting Trem2+ and Gdf15+ LAMs while preserving resident macrophages. This shift was accompanied by marked suppression of the Trem2 transcriptional program and down-regulation of PPAR-{gamma} and NR1H3 in LAMs and by impaired ASPC-LAM signaling pathways that normally drive LAM recruitment and activation. Proteomic profiling further showed that p21+/Tert ASPCs secreted markedly higher levels of proteins associated with non-conventional secretion, while extracellular matrix-associated factors and cytokines/chemokines including key mediators of ASPC-LAM communication such as Ccl2, C3, and Csf1 were substantially reduced. However, only p21+/Tert mice, and not p21+/TertCi mice, exhibited significant metabolic improvements, indicating that macrophage remodeling alone is insufficient to restore systemic metabolic function. Consistent with this, enhanced ASPC expansion and differentiation, supporting improved adipose-tissue remodeling, was observed exclusively in p21+/Tert obese mice. ConclusionsTERT remodels adipose tissue immunity independently of its enzymatic activity, and TERT-driven reprogramming of the ASPC secretome may emerge as a promising strategy to combat obesity-related metabolic dysfunction. HighlightsO_LIConditional expression of TERT or catalytically inactive TERTCi results in the depletion Trem2+ and Gdf15+ LAMs while preserving resident macrophages C_LIO_LITERT and TERTCi expression impairs ASPC-adipocyte/LAM communication pathways that normally drive LAM recruitment and activation. C_LIO_LIIn vitro, TERT conditional expression in ASPCs promotes non-conventional protein secretion and reduces the secretion of key mediators of ASPC-LAM communication C_LIO_LIOnly p21+/Tert mice, and not p21+/TertCi mice, exhibited enhanced ASPC expansion, improved adipose-tissue remodeling, and systemic metabolic benefits, demonstrating that macrophage remodeling alone is insufficient to restore metabolic function. C_LI

physiology↗

bioRxiv2025

The extracellular matrix drives guanylate production and protects pancreatic cancer cells from oxaliplatin-induced DNA damage.

The excessive production of extracellular matrix (ECM) and the metabolic adaptations in pancreatic ductal adenocarcinoma (PDAC) contribute individually to enhanced chemoresistance, dramatic tumor progression and dismal patient survival. However, ECM-driven metabolic alterations that promote chemoresistance in PDAC are so far unexplored. Here, we use in-vitro-generated ECM bio-scaffolds that recapitulate cell-ECM interactions and induce broad metabolic alterations in PDAC cells. High-throughput integration of multi-omics datasets coupled with metabolic tracing showed that the ECM enhances the generation of guanylates in PDAC cells, the accumulation of which alleviates oxaliplatin-induced DNA damage, and boosts PDAC cell proliferation. These events are guided by the guanosine monophosphate (GMP)-producing enzymes Impdh and Gmps, the expression of which correlated with that of matrisomal and DNA repair genes in PDAC patient samples. We propose that targeting ECM-driven metabolic processes, like the enhanced Impdh activity, may be an effective therapeutic approach for PDAC patients that bypasses the negative side effects of direct targeting of the ECM itself.

cancer biology↗

bioRxiv2025

TERT prevents obesity-induced metabolic disorders by promoting adipose stem cell expansion and differentiation

Obesity is linked to limited adipose tissue (AT) remodeling capacity, leading to hypertrophic adipocytes, senescence, and inflammation. We used a mouse model expressing mTert (p21+/Tert) from the Cdkn1a locus to investigate the role of mTERT in obesity-induced metabolic disorders. Conditional expression of mTERT reduces metabolic disorders associated with obesity. In AT, this is accompanied by a decrease in the number of senescent p21-positive cells, very short telomeres, and oxidative DNA damage. Single nucleus RNA-seq data reveal TERT expression attenuates senescence induced by HFD in particular in adipose stem and progenitor cells (ASPC). We show that ASPC expansion and differentiation are promoted in p21+/Tert obese mice, thereby reducing metabolic disorders. We further report that mTERT remodels the landscape of macrophages in AT of obese mice. Strikingly, inactivation of mTERT catalytic activity in p21+/Tert (p21+/TertCi) mice suppresses the promotion of adipocyte formation, but neither affects attenuation of senescence nor macrophage remodeling. These results highlight mTERTs canonical and non-canonical functions in reducing obesity-associated metabolic disorders. Conditional expression of TERT thus appears as a potential therapeutic option for obesity.

physiology↗