Biology subjects

De Andres-Laguillo, M.

Publications and source records attributed to De Andres-Laguillo, M..

3 recordsLinked to original sources

bioRxiv2025

Mitochondrial genetics defines anti-tumour immunity through mitochondrial ROS and PD-1 signalling

As central players in cell metabolism, mitochondria influence numerous aspects of health and disease, including the initiation and progression of cancer. Although mitochondrial DNA (mtDNA) mutations have been extensively documented in human cancers for decades, the functional impact of mitochondrial haplogroups on tumour biology remains largely unexplored. Here, we investigate the role of mitochondrial variability in tumour biology using conplastic mouse strains, which are animal models with identical nuclear genomes but different mtDNA haplotypes. We showed that the physiologically relevant variation in mitochondrial ROS (mROS) generation, associated with specific clusters of mtDNA single nucleotide polymorphisms (SNPs), modulated immune responses within the tumour microenvironment and altered tumour growth. We observed strain-dependent differences in the abundance of multiple immune subsets and in PD-1 expression in tumour-infiltrating lymphocytes (TILs). In addition, mtDNA haplotypes influenced cancer progression by modulating tumour angiogenesis through an mROS-independent mechanism. These findings connect nucleo-mitochondrial genetic variability to tumour progression, de novo vessel formation and anti-tumour immunity. Tumour immunotherapies should incorporate the spatial and temporal dynamics of cancer evolution and consider mitochondrial genetics as a targetable layer influencing treatment efficacy.

cancer biology↗

bioRxiv2025

Disrupted astrocyte-endothelial crosstalk drives hemangioblastoma lesions in VHL disease

Hemangioblastomas (HBs) are highly vascularized central nervous system (CNS) tumours that can become life-threatening, especially in the context of Von Hippel-Lindau (VHL) disease, caused by the loss of VHL function. The limited pharmacological options targeting VHL-HBs stem from an incomplete understanding of their cellular origin, development, and molecular pathogenesis. Here we use advanced mouse genetics to show that mosaic deletion of Vhl in Apln+ cells leads to the formation of precursor tumour-like lesions, composed by clusters of Vhl-knockout (VhlKO) astrocytes and surrounding Vhl-wild-type (VhlWT) vessels that become malformed, resembling early-stage HBs linked to VHL disease. VhlKO astrocytes morphologically and transcriptomically resembled the reactive astrocytes characteristic of ischemic CNS injury. They exhibited metabolic rewirement towards glycolysis and upregulation of cell growth pathways. They also expressed several secreted proangiogenic molecules that activate and prevent the normal maturation of neighbouring vessels, leading to VHL-HBs. Temporal conditional genetic analysis revealed that Vhl loss need to happen during postnatal development for HBs to form, and that lesions become quiescent in early adulthood. HIF-2 deletion, or MTORC1 inhibition with rapamycin, efficiently inhibited VHL-HBs growth and the associated vascular malformations. Our work shows that the loss of Vhl in single astrocytes induces their growth and pathogenic crosstalk with neighbouring endothelial cells, driving hemangioblastoma development in VHL disease. Our new somatic mosaic mouse models will also enable testing of novel drugs against this disease.

cancer biology↗

bioRxiv2025

Context-dependent response of endothelial cells to PIK3CA mutation

Cancer mutations in the PIK3CA gene cause congenital disorders. The endothelium is among the most frequently affected tissues in these disorders, displaying aberrant vascular overgrowth in the form of malformations. Pathological PIK3CA vascular phenotypes are found in veins and capillaries but rarely in arteries for reasons that are unclear at present. Here, using lineage tracing, we show that expression of mutated PIK3CAH1047R in endothelial cells leads to marked clonal expansions in capillary and venous endothelial cells. In contrast, mature arterial endothelial cells are refractory to PIK3CA mutation under these conditions and never display pathological phenotypes. Moreover, PIK3CAH1047Rexpression in arterial precursors interrupts arterial differentiation, thereby driving fate switch towards venous identity. This fate rewiring offers an additional layer of protection to prevent arterial damage in response to PIK3CA genetic perturbation. Molecularly, the PIK3CAH1047R-driven arterial-to-venous fate switch is orchestrated by upregulation of the vein-specifying transcription factor Nr2f2/COUP-TFII. Our findings reveal that pathogenic responses to PIK3CAH1047Rgreatly depend on the diferentation stage and fate trajectory of the targeted cell. Arteries are thus shielded against PIK3CA mutation, solving the long-standing question on the rarity of PIK3CA-related arterial malformations observed in patients.

developmental biology↗