Biology subjects

Vitte, J.

Publications and source records attributed to Vitte, J..

5 recordsLinked to original sources

bioRxiv2026

Merlin restoration prevents schwannoma progression in a genetically engineered mouse model of NF2-SWN

Patients with NF2-related schwannomatosis (NF2-SWN) present with hallmark bilateral vestibular schwannomas, but also schwannomas on other cranial, spinal, and peripheral nerves, as well as meningiomas and ependymomas, caused by germline mutations in the tumor suppressor gene NF2. Current therapies involving surgery and radiosurgery are effective for individual tumors but are not always a viable option for patients with multiple tumors, and harbor significant risk of neurological deficits and morbidity. Gene replacement therapy is becoming a promising new treatment strategy for several neurologic diseases. This study aims to understand if restoration of a functional merlin protein, gene product of the Nf2 gene, in Nf2-deficient tumor cells, can provide preclinical therapeutic efficacy in a NF2-SWN genetically engineered mouse model. We have developed a new Nf2 allele (Nf2FRT) that allows to conditionally restore Nf2 expression by activation with the Flp recombinase. We generated a new mouse model using the Nf2FRT allele in combination with Nf2flox and Postn-Cre alleles. Using the new conditional schwannoma mouse model Postn-Cre;Nf2FRT/flox;R26FlpoER, we validated the hypothesis that restoration of Nf2 reduces the growth of schwannoma. Demonstrating that merlin restoration effectively controls schwannoma growth is a crucial first step toward developing this concept as a new therapeutic strategy for potentially treating schwannomas. The new mouse model will be used to better understand the cellular and molecular mechanisms involved in stopping the growth of Nf2-deficient tumors.

cancer biology↗

bioRxiv2026

Quantitative imaging of schwannoma captures heterogeneity and accelerates preclinical testing, revealing distinct impacts of targeted therapies

Schwannomas are debilitating hallmarks of familial schwannomatoses and common sporadic tumors that form on spinal and cranial nerves. Drug-based therapies for schwannoma are desperately needed but their development has been extremely slow and disappointing, impeded particularly by the poorly understood and surprisingly complex and heterogeneous biology of schwannomas, and by the inefficient use of physiologically relevant in vivo preclinical models. We have addressed these gaps by developing a quantitative imaging-centered workflow that allows both a deep analysis of schwannoma development and accelerated preclinical testing in a widely used genetically engineered mouse model of neurofibromatosis type 2-related schwannomatosis (NF2-SWN). We deployed our workflow to study schwannoma development and to test two clinically relevant drugs (rapamycin and brigatinib) head-to-head. Our results uncovered the very early onset of heterogeneity and macrophage recruitment to initiating schwannomas, and the unexpectedly distinct impacts of the two drugs on both, highlighting the value of the pipeline for rapid, innovative future drug-testing.

cancer biology↗

bioRxiv2021

Cellular mechanisms of heterogeneity in NF2-mutant schwannoma

Schwannomas are common sporadic nervous system tumors and diagnostic features of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves and cause severe neurological deficits and significant morbidity. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. Despite their genetic uniformity schwannomas exhibit remarkable clinical and therapeutic heterogeneity, which has impeded the success of early rational therapies. An understanding of how heterogeneity develops in NF2-mutant schwannomas is critically needed to improve therapeutic options for these patients. We have found that loss of the membrane:actin cytoskeleton-associated NF2 tumor suppressor protein, merlin, yields unstable intrinsic polarity and enables Nf2-/- Schwann cells to adopt distinct programs of coordinated ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. We validated the heterogeneous distribution of biomarkers of these programs in human schwannoma tissue and took advantage of the synchronous development of multiple lesions in a well-studied mouse model to establish a quantitative pipeline that can be used to study how schwannoma heterogeneity evolves and impacts nerve function and therapeutic response in mouse, and ultimately human schwannomas. Our studies inform a mounting appreciation that intrinsic mechanisms are major contributors to heterogeneity across many human cancers.

cancer biology↗

bioRxiv2020

Stool serology: development of a non-invasive immunological method for the detection of Enterovirus-specific antibodies in Congo gorilla feces

The incidence of poliovirus has significantly reduced by as much as 99.9% globally. Alongside this, however, vaccine-associated paralytic poliomyelitis has emerged. Recently, a new recombinant virus (Enterovirus C/Poliovirus) was identified in humans working as eco-guards and in gorillas in Democratic Republic of Congo, including one gorilla with polio-like sequelae. A strain of this recombinant virus (Ibou002) was also isolated from gorilla faeces. In order to assess the potential role of poliovirus infection, we have developed and optimised a protocol, based on the lyophilisation and solubilisation of small volumes of stool extracts, to detect specific antibodies. First, total immunoglobulins was detected in the concentrated stool extracts. Specific antibodies were then detected in 4/16 gorilla samples and 2/3 human samples by western blot using both the polio vaccine antigen and the Ibou002 antigen and by ELISA using the polio vaccine antigen. Humoral responses were greater with the Ibou002 antigen. We therefore suggest that this recombinant virus could lead to a polio-like disease in the endangered western lowland gorilla. The development of a non-invasive method to detect microorganism-specific immunoglobulins from faecal samples opens up new perspectives for the exploration of humoral responses of pathogens in animals and a greater understanding of zoonotic infectious diseases.

microbiology↗

bioRxiv2020

Monocytes and macrophages, targets of SARS-CoV-2: the clue for Covid-19 immunoparalysis

To date, the Covid-19 pandemic affected more than 18 million individuals and caused more than 690, 000 deaths. Its clinical expression is pleiomorphic and severity is related to age and comorbidities such as diabetes and hypertension. The pathophysiology of the disease relies on aberrant activation of immune system and lymphopenia that has been recognized as a prognosis marker. We wondered if the myeloid compartment was affected in Covid-19 and if monocytes and macrophages could be infected by SARS-CoV-2. We show here that SARS-CoV-2 efficiently infects monocytes and macrophages without any cytopathic effect. Infection was associated with the secretion of immunoregulatory cytokines (IL-6, IL-10, TGF-{beta}) and the induction of a macrophagic specific transcriptional program characterized by the upregulation of M2-type molecules. In addition, we found that in vitro macrophage polarization did not account for the permissivity to SARS-CoV-2, since M1-and M2-type macrophages were similarly infected. Finally, in a cohort of 76 Covid-19 patients ranging from mild to severe clinical expression, all circulating monocyte subsets were decreased, likely related to massive emigration into tissues. Monocytes from Covid-19 patients exhibited decreased expression of HLA-DR and increased expression of CD163, irrespective of the clinical status. Hence, SARS-CoV-2 drives circulating monocytes and macrophages inducing immunoparalysis of the host for the benefit of Covid-19 disease progression.

immunology↗