Biology subjects

Andre, P.

Publications and source records attributed to Andre, P..

3 recordsLinked to original sources

bioRxiv2025

ALK1-BMPRII agonism by clustering bispecific antibodies treats hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is characterized by arteriovenous malformations (AVMs) and severe bleeding caused by loss-of-function mutations in the ALK1 receptor pathway. We developed clustering agonist bispecific antibodies (BsAbs) targeting ALK1 and its activating partner, the Ser/Thr receptor kinase BMPRII. These BsAbs induced ALK1-BMPRII proximity association, stimulated the downstream Smad1/5/8 signaling cascade, and treated HHT pathologies in various mouse models. BsAb treatment reduced AVM burden by up to 95% in HHT mice, preventing anemia, cardiomegaly, and premature death. The BsAbs also enhanced Smad1/5/8 signaling in endothelial cells derived from HHT patients with ALK1 mutations and prevented retinal AVMs in a newly developed knock-in mouse carrying an HHT-causing ALK1 mutation. These findings establish ALK1-BMPRII agonism as a promising therapeutic strategy for HHT.

cell biology↗

bioRxiv2022

Ts66Yah, a refined Ts65Dn DS mouse model, unravels genetic interaction between regions homologous to Human chromosome 21 and the Scaf8-Pde10a genetic interval.

Down syndrome is caused by trisomy of human chromosome 21 (Hsa21). The understanding of phenotype-genotype relationships, the identification of driver genes and various proof-of-concepts for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to the human DS features. It carries an additional minichromosome with the Mir155 to Zbtb21 region of mouse chromosome 16 (Mmu16), homologous to Hsa21, encompassing around 90 genes, fused to the centromeric part of mouse chromosome 17 (Mmu17) fromPisd-ps2/Scaf8 to Pde10a, containing 46 genes, not related to Hsa21. Here, we report the investigation of a new model, Ts66Yah, generated by CrispR/Cas9 without the genomic region unrelated to Hsa21 on the minichromosome. As expected, Ts66Yah replicated DS cognitive features. However, certain phenotypes related to increased activity, spatial learning and molecular signatures, were changed suggesting genetic interactions between the Mir155-Zbtb21 and the Scaf8-Pde10a interval. Thus, Ts66Yah mice have a stronger construct and face validity for mimicking consequences of DS genetic overdosage. Furthermore, this report is the first to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to Hsa21.

genetics↗

bioRxiv2020

Lipogenesis and innate immunity in hepatocellular carcinoma cells reprogrammed by an isoenzyme switch of hexokinases

During the cancerous transformation of normal hepatocytes into hepatocellular carcinoma (HCC), the enzyme catalyzing the first rate-limiting step of glycolysis, namely the glucokinase (GCK), is replaced by the higher affinity isoenzyme, hexokinase 2 (HK2). The transcriptomic analysis of HCC tumors shows that highest expression level of HK2 in tumor lesions is inversely correlated to GCK expression, and is associated to poor prognosis for patient survival. To further explore functional consequences of the GCK-to-HK2 isoenzyme switch occurring during carcinogenesis, HK2 was knocked-out in the HCC cell line Huh7 and replaced by GCK, to generate the Huh7-GCK+/HK2- cell line. HK2 knockdown and GCK expression rewired central carbon metabolism, stimulated mitochondrial respiration and restored essential metabolic functions of normal hepatocytes such as lipogenesis, VLDL secretion, glycogen storage. It also reactivated innate immune responses and sensitivity to natural killer cells, showing that consequences of the HK switch extend beyond metabolic reprogramming.

cancer biology↗