Biology subjects

Schcolnik-Cabrera, A.

Publications and source records attributed to Schcolnik-Cabrera, A..

6 recordsLinked to original sources

bioRxiv2026

eIF4A inhibition disrupts resistance-associated translational and metabolic programs in BRAF-mutant melanoma

Acquired resistance to mitogen-activated protein kinase (MAPK) pathway inhibitors remains a major barrier to durable control of BRAF-mutant melanoma. Although resistance mechanisms are heterogeneous, they converge on adaptive programs that support survival, phenotypic plasticity, and metabolic fitness. We asked whether eukaryotic translation initiation factor 4A (eIF4A)-dependent mRNA translation represents a shared vulnerability of kinase inhibitor-resistant melanoma. Using matched BRAFV600E A375 and BRAF inhibitor-resistant A375R cells together with additional melanoma models, we integrated pharmacological and functional assays with polysome-associated RNA sequencing, quantitative proteomics, bioenergetic profiling, metabolomics, [U-13C5]glutamine tracing, and xenograft studies. Melanoma cells remained sensitive to multiple eIF4A inhibitors regardless of their responsiveness to BRAF inhibition. The eIF4A inhibitor CR-1-31-B rapidly reduced nascent protein synthesis when used alone in A375 cells and when added to the BRAF inhibitor PLX4032 in A375R cells; it also reduced BCL-2, CDK4, and cyclin D3 abundance, suppressed clonogenic growth, and induced apoptosis. Integrated analysis showed that acquired resistance involved broad RNA-abundance remodeling with superimposed changes in translational efficiency and buffering, affecting survival, extracellular-matrix and plasticity programs, and mitochondrial and metabolic functions. In resistant cells, CR-1-31-B induced early transcript-selective translational changes, accompanied at later time points by RNA-abundance and proteome remodeling. Publicly annotated 5' untranslated regions (5'UTRs) of CR-1-31-B-sensitive transcripts were enriched for purine-rich sequence architecture and local structural complexity. eIF4A inhibition preferentially attenuated the expression of proteins acquired during resistance and imposed a lower-output metabolic state in sensitive and resistant cells, reducing tricarboxylic-acid-cycle and pentose-phosphate-pathway metabolite pools and restricting intracellular glutamine-carbon transfer downstream of uptake. In A375 xenografts, CR-1-31-B delayed tumor growth, while its combination with PLX4720 produced deeper and more sustained tumor control and prolonged tumor endpoint-free survival compared with PLX4720 alone. These findings show that multiple resistance-associated programs spanning signaling, cell survival, and metabolism share a dependency on eIF4A-dependent translation and provide a preclinical rationale to test whether adding eIF4A inhibition can prolong responses to MAPK-targeted therapy in melanoma.

cancer biology↗

bioRxiv2026

Rasal1 impairment unleashes anticancer immunity - a focus on T cells

Immune checkpoint blockade (ICB) has demonstrated clinical efficacy in several cancers, including melanoma, lung, colorectal, and liver malignancies. However, a substantial proportion of patients fail to respond, underscoring the need for alternative immunotherapeutic strategies capable of overcoming resistance to conventional checkpoint inhibition. One such strategy involves targeting intracellular inhibitory immune checkpoints that regulate effector lymphocyte function. Rasal1, a Ras GTPase-activating protein, has been shown to negatively regulate T cell-mediated antitumor immunity. In this study, we further characterized the impact of Rasal1 impairment on tumor progression, T cell stemness, and effector function. Using an endonuclease-mediated mutation targeting the C2 domain of Rasal1, we demonstrate that Rasal1-impaired (Rasal1i) mice exhibit significantly reduced tumor growth across multiple murine cancer models. Rasal1i mice displayed increased intratumoral CD8+ T cell accumulation, activation, cytolytic capacity, and enhanced Wnt signaling. Tumor-infiltrating lymphocytes additionally exhibited increased progenitor and stem-like memory phenotypes. Notably, Rasal1 inhibition prolonged survival and potentiated PD-1 therapy in a resistant PD-L1-expressing B16F10 melanoma model. Collectively, these findings identify Rasal1 as an intracellular inhibitory immune checkpoint that constrains T cell stemness and antitumor function, and support its further evaluation as a therapeutic target for cancer immunotherapy.

immunology↗

bioRxiv2024

Metabolic reprogramming and synergistic cytotoxicity of genistein and chemotherapy in human breast cancer cells

Breast cancer (BCa) is a heterogeneous disease, initially responsive to hormone therapy but often developing resistance to both hormonal and chemotherapy treatments. Novel therapeutic strategies are needed for drug-resistant BCa. Genistein, a phytoestrogen structurally similar to estrogen, competes with estrogen for receptor binding and exhibits anti-cancer effects. In this study, we investigated the cellular and metabolic impacts of genistein, alone or in combination with chemotherapy, in two human BCa cell lines--one estrogen receptor-positive (ER+) and one estrogen receptor-negative (ER-). We observed a strong synergistic effect on cell viability at low concentrations of genistein and chemotherapy, resulting in reduced clonogenic capacity and impaired cell migration. Genistein alone modulated cellular energy metabolism, notably reducing ATP production in MCF7 (ER+) cells. This metabolic shift was linked to a decreased dependence on fatty acids for energy, coupled with a decrease in the rate-limiting mitochondrial translocase CPT1 required for fatty acid oxidation, alongside with an increase in intracellular fatty acid levels. While the most significant changes occurred in ER+ cells, ER- cells also showed responses to genistein treatment. Collectively, our findings suggest that low dose genistein, in combination with conventional chemotherapy, induces synergistic anti-cancer effects, promoting cellular senescence. This effect may be partly mediated by a reduced reliance on fatty acid metabolism in BCa cells.

cancer biology↗

bioRxiv2024

Maternal humoral factors modulate offspring gut immune homeostasis to mitigate diabetes development

Environmental risk factors possess the potential to modulate the pathogenesis of type I diabetes (T1D). Foremost among these factors are early life influences impacting the gastrointestinal (GI) tract. During infancy, both the microbiota and immune system are influenced by maternal factors contributing to key events in the neonatal GI tract. Despite the well-known importance of maternal factors on infant immune development, whether maternal immune dysregulation and dysbiosis can perpetuate the same in offspring remains largely unknown. To explore how these maternal factors impact offspring disease development, we used IgA-deficiency induced maternal dysbiosis in Non-Obese Diabetic (NOD) dams to study T1D development in their progeny. We found that maternal dysbiosis and absence of IgA led to changes in IgA-sufficient offspring immune development resulting in heightened GI immune activity. Maternal dysbiosis also contributed to altered microbiome establishment in progeny, such that pups exhibited reduced colonic abundance of Akkermansia muciniphila and Clostridoides difficile. In adulthood, these mice exhibited a lowered incidence of T1D. This protection was replicated by fostering high incidence offspring to dysbiotic dams, prompting us to propose that altered breast milk composition in dysbiotic dams can influence immune development and microbiome establishment in offspring, contributing to T1D resistance.

immunology↗

bioRxiv2024

The role of YAP/TAZ signaling in dendritic cell-mediated pathogenesis of insulin resistance and non-alcoholic fatty liver disease

Obesity and insulin resistance (IR) are global health challenges linked to metabolic diseases, such as type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). High-caloric intake, which is associated to NAFLD, induces adipocyte hypertrophy and inflammation, triggering dendritic cell (DC) activation and systemic inflammation. DC exacerbate inflammation by promoting pro-inflammatory responses, aggravating IR and NAFLD progression. NAFLD is characterized by liver fibrosis, which alters tissue stiffness that can trigger mechanosensing pathways such as the Hippo pathway in immune cell types. In this work we explored the roles of key mediators of the Hippo pathway, YAP and TAZ, in DCs within the context of liver fibrosis, obesity and IR, using a model of NAFLD induced by feeding a high fat high sucrose diet. Our findings indicate that specific deletion of YAP and/or TAZ in DCs had minimal impact on IR development and metabolic tissue inflammation. We conclude that YAP and TAZ have limited and possibly redundant roles in the immune pathophysiology of NAFLD and IR.

immunology↗

bioRxiv2024

O-GlcNAcylation of FOXK1 orchestrates the E2F pathway and promotes oncogenesis

Gene transcription is a highly regulated process, and deregulation of transcription factors activity underlies numerous pathologies including cancer. Albeit near four decades of studies have established that the E2F pathway is a core transcriptional network that govern cell division in multi-cellular organisms1,2, the molecular mechanisms that underlie the functions of E2F transcription factors remain incompletely understood. FOXK1 and FOXK2 transcription factors have recently emerged as important regulators of cell metabolism, autophagy and cell differentiation3-6. While both FOXK1 and FOXK2 interact with the histone H2AK119ub deubiquitinase BAP1 and possess many overlapping functions in normal biology, their specific functions as well as deregulation of their transcriptional activity in cancer is less clear and sometimes contradictory7-13. Here, we show that elevated expression of FOXK1, but not FOXK2, in primary normal cells promotes transcription of E2F target genes associated with increased proliferation and delayed entry into cellular senescence. FOXK1 expressing cells are highly prone to cellular transformation revealing important oncogenic properties of FOXK1 in tumor initiation. High expression of FOXK1 in patient tumors is also highly correlated with E2F gene expression. Mechanistically, we demonstrate that FOXK1, but not FOXK2, is specifically modified by O-GlcNAcylation. FOXK1 O-GlcNAcylation is modulated during the cell cycle with the highest levels occurring during the time of E2F pathway activation at G1/S. Moreover, loss of FOXK1 O-GlcNAcylation impairs FOXK1 ability to promote cell proliferation, cellular transformation and tumor growth. Mechanistically, expression of FOXK1 O-GlcNAcylation-defective mutants results in reduced recruitment of BAP1 to gene regulatory regions. This event is associated with a concomitant increase in the levels of histone H2AK119ub and a decrease in the levels of H3K4me1, resulting in a transcriptional repressive chromatin environment. Our results define an essential role of O-GlcNAcylation in modulating the functions of FOXK1 in controlling the cell cycle of normal and cancer cells through orchestration of the E2F pathway.

molecular biology↗