Biology subjects

Hernandez-Sanchez, M.

Publications and source records attributed to Hernandez-Sanchez, M..

4 recordsLinked to original sources

bioRxiv2026

MYC overexpression drives poor prognosis and differential sensitivity to treatments according to TP53 status in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasm with very heterogeneous clinical and biological behavior. Among molecular variables, TP53 alterations are well-established adverse prognostic markers; however, MYC activation, which has been linked to disease progression, has not been completely defined in terms of clinical and biological impact, particularly in relation to TP53 status. Here, we investigated the effects of MYC overexpression according to TP53 status using clinical and transcriptomic data from CLL patients and novel cellular models. CLL patients with TP53WT and MYC overexpression exhibited significantly shorter time to first treatment and overall survival, indicating an aggressive disease course comparable to that of patients with TP53 alterations. Consistently, MYC overexpression in in vitro TP53WTmodels was associated with increased proliferation, enrichment of AKT/mTOR signaling and upregulation of genes involved in leukemogenesis and tumor progression such as FOXO6. Moreover, MYC overexpression was associated with increased sensitivity to venetoclax in TP53WT cells. By contrast, the concurrence of MYC overexpression and TP53 dysfunction conferred resistance to conventional CLL therapies such as BCL2 or BTK inhibitors. Of note, we identified a glycolysis inhibitor, in monotherapy or combined with BKT inhibitors, as a potential therapeutic strategy for CLL patients harboring MYC overexpression and TP53 alterations.

cancer biology↗

bioRxiv2026

Context-dependent tonic signaling shapes the performance and manufacturability of a 4-1BB- based HER2 CAR-T cell therapy

The development of clinically effective CAR-T cell therapies for solid tumors requires careful optimization of receptor design, functional fitness, and manufacturability. While advancing low-affinity HER2-targeting CAR-T cells toward clinical application, we found that the candidate with the strongest in vivo antitumor activity--comprising a CD8 hinge and transmembrane region and a 4-1BB co-stimulatory domain--exhibited measurable tonic signaling. This basal antigen-independent signaling, likely driven by high CAR surface expression, was associated with increased apoptosis and reduced ex vivo expansion under research-grade manufacturing conditions. Modification of the transmembrane domain reduced CAR surface expression but did not alleviate tonic signaling and instead impaired antitumor activity. By contrast, transient pharmacologic inhibition of CAR signaling with dasatinib rescued expansion and reduced apoptosis in small-scale research cultures. Notably, these tonic-signaling-associated defects were largely absent during large-scale, GMP-compliant manufacturing, which enabled robust CAR-T cell expansion without additional benefit from dasatinib supplementation. Together, these findings show that tonic signaling is not inherently detrimental to CAR-T cell performance and that its functional consequences are highly dependent on manufacturing context. Our study underscores the importance of evaluating CAR candidates within clinically relevant production platforms and supports the advancement of this 4-1BB-based HER2-specific CAR-T cell product toward clinical testing.

immunology↗

bioRxiv2024

The mechanoreceptor PIEZO1 is a novel oncogene in glioma by promoting astrocyte reactivity

Glioblastoma is the most common and aggressive brain tumour in adults. Despite advances in its molecular characterization, there is a gap-of-knowledge in the identification of bona fide drivers and potential therapeutic targets that could change the clinical picture. Mechanoreception, the sensing of mechanical cues by cells, has proven to be an important factor in cell biology, particularly in cancer. Piezo1 is a mechanoreceptor found in all cells and seems to play a role in different cancer types, such as gastric, breast or lung cancer. However, there is still lack of understanding about its role in the onset and progression of glioblastoma. Here, we show that Piezo1 acts as an oncogene in glioma by potentially promoting chronic astrocyte reactivity. We developed a novel transgenic murine model of Piezo1 overexpression in astrocytes. These animals had a significant reduction in overall survival and developed glioma with a penetrance of 30%. We also developed a PIEZO1-overexpressing U251 cell line and found that it had a more aggressive and reactive-like phenotype. Finally, we correlated the levels of PIEZO1 with the clinical outcome of a cohort of glioblastoma patients and observed that PIEZO1 is a biomarker of worse prognosis. However, PIEZO1 only correlated with worse prognosis in male patients, suggesting a sexual dimorphism. In conclusion, we identified Piezo1 as a bona fide driver of glioma, revealing its implication in astrocyte reactivity and identifying it as a biomarker for glioma in the clinic.

cancer biology↗

bioRxiv2023

The nucleolar aberrancies that drive ribosome impairment induced by RNA binding proteins are hallmarks of aging

The nucleolus is a dynamic structure where ribosome subunits are produced. Indeed, nucleoli respond to any change in cellular homeostasis by altering the rate of ribosome biogenesis, thus working as a stress sensor. Therefore, an imbalance in ribosome biogenesis promotes changes in morphology and function and can evoke a nucleolar stress response. Changes in the structure and composition of nucleoli impair ribosome biogenesis and have been described as nucleolar stress, a mechanism related to aging and cancer. Here, we show the role of the RNA binding protein Hnrnpk in nucleolar dynamics and ribosome function. Hnrnpk is a ribonucleoprotein in charge of escorting nascent transcripts to its processing and nuclear export to ribosomes. When Hnrnpk is overexpressed, the nucleolus is altered and shows stress-like phenotype, with accumulation and delocalization of components such as Ncl, driving ribosome biogenesis impairment and halting protein translation. Nucleolin haploinsufficiency is correlated with enlarged nucleoli, increased ribosome components and translation and induces a reduction in lifespan. Thus, gain of Ncl generated by Hnrnpk overexpression can cause ribosome biogenesis defects associated with ribosome impairment leading to ribosomopathies and bone marrow failure syndrome. Aging and bone marrow failure share common biological hallmarks. Indeed, Hnrnpk overexpression and nucleolar stress trigger cell cycle arrest and senescence of the cells, a feature of both processes. Together, these findings support the idea that nucleolar abnormalities contribute to ribosome impairment, thus triggering the onset of hematopoiesis and the aging process. Here, we decipher a novel master regulator of this mechanism: Hnrnpk.

molecular biology↗