Biology subjects

Del Sal, G.

Publications and source records attributed to Del Sal, G..

3 recordsLinked to original sources

bioRxiv2026

CKII-Phosphorylated HPV-16 E7 Disrupts Planar Cell Polarity by Recruiting Vangl1

High-risk human papillomaviruses (HPVs) depend on continuous expression of the E6 and E7 oncoproteins to sustain malignant transformation. The high-risk E7 oncoprotein is multifunctional, and its phosphorylation by Casein Kinase II (CKII) amplifies its oncogenic potential. Here, we identify Vangl1, a core planar cell polarity (PCP) scaffold protein, as a novel, phosphorylation-dependent interactor of HPV-16 E7. CKII-mediated phosphorylation is required for Vangl1 recruitment, and this interaction is largely selective for HPV-16 E7. In cervical cancer cells, E7 expression profoundly disrupts Vangl1 homeostasis, producing a biphasic proteostatic imbalance in which phosphorylated Vangl1 is aberrantly retained. This retention parallels E7 stability, revealing a reciprocal oncogenic stabilization. E7 also impairs Vangl1 trafficking and localization by co-opting the clathrin adaptor subunit AP1M1. Functionally, Vangl1 depletion mirrors E6/E7 loss in CaSki spheroids by disrupting spheroid architecture, reducing invasiveness, and increasing chemosensitivity. Taken together, these findings position Vangl1 as a central effector in E7-mediated cervical transformation and invasive progression. TeaserE7s control of Vangl1 reveals a polarity-remodeling mechanism that drives cervical cancer invasion and progression.

cancer biology↗

bioRxiv2025

Human liver organoids uncover ductular reaction in Wolman disease and inform gene therapy design

Wolman disease (WD), the severe infantile form of lysosomal acid lipase deficiency, is a rare metabolic disorder caused by inactivating mutations in the LIPA gene. Although WD is characterized by profound hepatic dysfunction, experimental human systems capable of modelling multicellular liver pathology and supporting therapeutic testing remain limited. Here, we generated an isogenic human model of WD by introducing LIPA loss-of-function mutations into induced pluripotent stem cells and differentiating them into multicellular human liver organoids (HLO). LIPA-deficient HLO preserved hepatic lineage specification while recapitulating key biochemical and cellular features of WD, including loss of LIPA activity, lysosomal expansion, lipid accumulation, and activation of inflammatory and fibrogenic programs. Single-cell RNA sequencing resolved cell-type-specific disease states across hepatocyte-, stromal-, and biliary-like populations, revealing the emergence of a reactive biliary program consistent with ductular reaction, a complex tissue response associated with chronic liver injury. Importantly, this reactive biliary phenotype was supported by targeted gene-expression analysis in WD liver organoids and independently validated in liver tissue from mouse models and WD patients. Isolated LIPA-deficient cholangiocyte organoids failed to reproduce the DR-associated program, indicating that this response depends on multicellular interactions within the hepatic microenvironment rather than on biliary cell-autonomous dysfunction alone. Consistently, hepatocyte-directed AAV-mediated restoration of LIPA expression attenuated metabolic stress, inflammatory and fibrogenic programs, and suppressed ductular reaction both in organoids and in vivo. Together, these findings establish multicellular human liver organoids as a physiologically relevant platform for modelling emergent tissue-level responses in WD and for evaluating therapeutic rescue strategies in a human context.

pathology↗

bioRxiv2023

Pauperization of Emerin from nuclear envelope drives prostate cancer cell migration and invasiveness

Micronuclei (MN) can arise from many causes, including the breakage of aberrant cytokinetic chromatin bridge. The frequent observation of MN in tumors raises the specter that they might not merely be passive elements but could instead play active roles in tumor progression. Here, we test the hypothesis that the presence of micronuclei could induce specific phenotypic and functional changes to the cell and lead to increased cancer invasive potential. With a variety of imaging and molecular methods in vitro and in clinical samples from prostate cancer (PCa) patients, we show that chromosome bridge resolution can lead to EMD accumulation and formation of EMD-rich MN. Such structure is negative for Lamin A/C and positive for LBR and Sec6{beta}. It can cause EMD pauperization from NE affecting migratory and invasive properties of a cell and can be translated to PCa patients poor prognosis.

cancer biology↗