Biology subjects

Calderon, V.

Publications and source records attributed to Calderon, V..

3 recordsLinked to original sources

bioRxiv2026

The lncRNA FENDRR fine-tunes FOXF1 protein levels through a negative feedback loop governing human embryonic lung fibroblast-to-myofibroblast transition

Precise control of transcription factor dosage is critical for lung mesenchymal development. The forkhead box transcription factor FOXF1 is a dosage-sensitive regulator of pulmonary vascularization and fibroblast differentiation, with haploinsufficiency causing the lethal neonatal disorder alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). A syntenically conserved long noncoding RNA (lncRNA), FENDRR, is divergently transcribed [~]1.7 kb upstream of FOXF1. Notably, ACDMPV-associated chromosomal deletions disrupting FENDRR or a distal enhancer regulating both FENDRR and FOXF1 have been identified. Consistent with a role in lung development, selective deletion of Fendrr in mice causes neonatal lethality with lung growth defects, as well as alveolar and vascular abnormalities. Here, we define the conserved expression patterns, isoform diversity, and subcellular localization of FENDRR and FOXF1 across human and murine embryonic lung cell types. Functional perturbation reveals a bidirectional regulatory circuit in which FOXF1 promotes FENDRR transcription, while FENDRR limits FOXF1 protein abundance without affecting mRNA levels. Transcriptomic analyses demonstrate overlapping target gene networks and opposing effects on fibroblast-to-myofibroblast differentiation. These findings uncover a rheostat-like regulatory layer by which the lncRNA FENDRR fine-tunes FOXF1 protein dosage to influence lung fibroblast cell fate response and offers additional context for the significance of FOXF1-FENDRR dysregulation in ACDMPV.

molecular biology↗

bioRxiv2025

Human RIG-I deficiency confers susceptibility to Kaposi Sarcoma via loss of latency control

Kaposi sarcoma (KS), caused by the DNA-virus Kaposis sarcoma-associated herpesvirus (KSHV), occurs during T cell immunosuppression (HIV, transplant) or sporadically in some immunocompetent and aging individuals (endemic, classic KS respectively). In absence of known T cell immunosuppression KS pathogenesis remains enigmatic. KS therapy with topical or oral retinoid medication, or recombinant alpha interferon, can induce remission and suggests the involvement of two signalling pathways. Retinoic acid-inducible gene-I (RIG-I) encoded by DDX58 is canonically a sensor of RNA-viruses, its function in human immunity against DNA-viruses remains poorly defined. We report a patient with classic KS, carrying a homozygous nonsense (p.Q393*) mutation in DDX58, abolishing RIG-I expression and specifically impairing RIG-I agonist responses. In isogenic cell models, loss of RIG-I compromised responses during both KSHV primary infection and viral reactivation, diminishing induction of type I interferons and interferon-stimulated genes, skewing to a persistent latent viral gene program, and dysregulating cellular pro-oncogenic pathways by transcriptomic and proteomic profiling. This work defines the first innate immunodeficiency underlying classical KS, revealing RIG-Is role in KSHV immunopathogenesis and expanding its function in human antiviral immunity beyond RNA-viruses, while identifying promising therapeutic targets. Significance statementRIG-I deficiency causes classic KS by failing to control KSHV infection and reactivation, expanding its role beyond RNA-viruses.

immunology↗

bioRxiv2023

Targeting the dependence on PIK3C3-mTORC1 signaling in dormancy-prone breast cancer cells blunts metastasis initiation

Halting breast cancer metastatic relapses following primary tumor removal and the clinical dormant phase, remains challenging, due to a lack of specific vulnerabilities to target during dormancy. To address this, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). We discovered that loss of class-III PI3K, Pik3c3, revealed a unique vulnerability in 4T07 cells. Surprisingly, dormancy-prone 4T07 cells exhibited higher mTORC1 activity than 4T1 cells, due to lysosome-dependent signaling occurring at the cell periphery. Pharmacological inhibition of Pik3c3 counteracted this phenotype in 4T07 cells, and selectively reduced metastasis burden only in the 4T07 dormancy-prone model. This mechanism was also detected in human breast cancer cell lines in addition to a breast cancer patient-derived xenograft supporting that it may be relevant in humans. Our findings suggest dormant cancer cell-initiated metastasis may be prevented in patients carrying tumor cells that display PIK3C3-peripheral lysosomal signaling to mTORC1. Statement of SignificanceWe reveal that dormancy-prone breast cancer cells depend on the class III PI3K to mediate a constant peripheral lysosomal positioning and mTORC1 hyperactivity. Targeting this pathway might blunt breast cancer metastasis.

cancer biology↗