Biology subjects

Tabernero, A.

Publications and source records attributed to Tabernero, A..

3 recordsLinked to original sources

bioRxiv2026

Neuro-mimetic reprogramming and epigenetic unlocking drive lung cancer stem cell adaptation to the brain microenvironment

Brain metastasis represents a lethal complication of non-small cell lung cancer, driven by the ability of disseminated tumor cells to colonize the central nervous system microenvironment. Although cancer stem cells (CSCs) are recognized as key drivers of metastatic initiation, whether their contact with the brain parenchyma induces terminal differentiation or adaptive plasticity remains controversial. Here, using an in vivo model of lung-derived CSCs injected intracranially, combined with quantitative total proteomics and phosphoproteomics, we demonstrate that contact with the brain niche triggers a neuro-mimetic reprogramming rather than terminal differentiation. Lung CSCs desensitize their systemic metastatic program while epigenetically unlocking neural stem cell networks, characterized by the upregulation of Ngfr, Fabp7, Pbx3, Vgf, and S100b, concurrent with the downregulation of the DNA methyltransferase Dnmt3a and the cytosolic exclusion of Id1. Phosphoproteomic profiling revealed post-translational adaptations, highlighted by hyperphosphorylation of Nestin at S957 and S963. Furthermore, kinase substrate enrichment analysis uncovered high activity of Prkcq (PKC{theta}) and Map3k7 (TAK1), shifting the cellular state toward structural remodelling and microenvironmental stress tolerance. Functional validation assays using selective inhibitors confirmed that these kinase networks represent adaptive liabilities within tissue constraints rather than basic in vitro survival requirements. Together, our findings demonstrate that lung CSCs exploit a phenotypic plasticity to adapt to the brain niche, acquiring a neural-glial disguise that supports vascular co-option, immune evasion, and metastatic colonization.

cancer biology↗

bioRxiv2023

Single-nucleus RNA sequencing provides insights into the GL261-GSC syngeneic mouse model of glioblastoma

Glioblastoma (GBM) is an aggressive tumor with very bad prognosis. The urgent need to find new effective therapies is challenged by the unique characteristics of GBM, including high intra and intertumoral heterogeneity. Using single-nucleus transcriptomics (snRNA-seq), we characterized the panorama of a preclinical immunocompetent murine model based in the implantation of mouse glioblastoma stem cells (GL261-GSCs) into the brain parenchyma. Additionally, we performed Visium spatial transcriptomics in the in vivo model to confirm the location of annotated cells. To understand the technical bias of this approach, we performed two scRNA-seq methods in GBM cells. We thoroughly characterized the tumor microenvironment (TME) at early and late stages of tumor development and upon treatment with temozolomide (TMZ), the standard of care for patients with GBM, and with Tat-Cx43266-283, a promising experimental treatment. We identified prominent GBM targets that can be addressed using this preclinical model, such as Grik2, Nlgn3, Gap43 or Kcnn4, which are involved in electrical and synaptic integration of GBM cells into neural circuits, as well as the expression of Nt5e, Cd274 or Irf8, which indicates the development of immune evasive properties in these GBM cells. In agreement, snRNA-seq unveiled high expression of several immunosuppressive-associated molecules in immune cells, such as Csf1r, Arg1, Mrc1 and Tgfb1, suggesting the development of an immunosuppressive microenvironment. We also show the landscape of cytokines, cytokine receptors, checkpoint ligands and receptors in tumor and TME cells, which are crucial data for a rational design of immunotherapy studies. Thus, Mrc1, PD-L1, TIM-3 or B7-H3 are among the immunotherapy targets that can be addressed in this model. Finally, the comparison of the preclinical GL261-GSC GBM model with human GBM subtypes unveiled important similarities with the recently identified TMEmed human GBM, indicating that preclinical data obtained in GL261-GSC GBM model might be applied to TMEmed human GBM, improving patient stratification in clinical trials. In conclusion, this work provides crucial information for future preclinical studies in GBM improving their clinical application.

neuroscience↗

bioRxiv2019

TAT-Cx43266-283 impairs metabolic plasticity in glioma stem cells in vitro and in vivo

Glioblastoma is the most aggressive primary brain cancer, with a median survival of 1 to 2 years1. These tumours contain glioma stem cells (GSCs), which are highly tumorigenic, resistant to conventional therapies2, 3, and exhibit metabolic plasticity to adapt to challenging environments4, 5. GSCs can be specifically targeted by a short cell-penetrating peptide based on connexin43 (Cx43) (TAT-Cx43266-283) that reduces tumour growth and increases survival in preclinical models6 via c-Src inhibition7. Because several reports revealed poor clinical efficacy of various antitumoral drugs due to metabolic rewiring in cancer cells8-10, we investigated the effect of TAT-Cx43266-283 on GSC metabolism and metabolic plasticity. Here we show that TAT-Cx43266-283 decreases GSC glucose uptake and oxidative phosphorylation without a compensatory increase in glycolysis, with no effect on neuron or astrocyte metabolism. GSC changes were mediated by decreased hexokinase (HK) activity and aberrant mitochondrial localization, ultrastructure and function. Moreover, TAT-Cx43266-283 reduced GSC growth and survival under different nutrient availability conditions by impairing the metabolic plasticity needed to exploit glucose as an energy source in the absence of other nutrients. Finally, GSCs intracranially implanted into mice together with TAT-Cx43266-283 showed decreased levels of important targets for cancer therapy, such as HK-211, 12 and glucose transporter 3 (GLUT-3)13, evidencing the reduced ability of treated GSCs to survive in challenging environments. Our results confirm the value of TAT-Cx43266-283 for glioma therapy alone or in combination with therapies whose resistance relies on metabolic adaptation. More importantly, these results allow us to conclude that the advantageous metabolic plasticity of GSCs is a targetable vulnerability in malignant gliomas.

cancer biology↗