Biology subjects

Martinez-Useros, J.

Publications and source records attributed to Martinez-Useros, J..

5 recordsLinked to original sources

bioRxiv2025

FOLFIRINOX Combined with GPX4 Inhibition Induces Ferroptosis and Defines Redox-Based Therapeutic Subgroups in Pancreatic Cancer

PurposeFerroptosis is a regulated form of cell death with therapeutic relevance in pancreatic ductal adenocarcinoma where Redox accumulation contributes to chemoresistance and poor prognosis. In this study, we aimed to evaluate the efficacy of combining the FOLFIRINOX regimen with a GPX4 inhibitor, RSL3, and to identify Redox-related predictive and prognosis biomarkers. Experimental DesignA combination of in vitro and in vivo models were used to evaluate oxidative stress, apoptosis, ferroptosis, and the modulation of Redox proteins, GPX4 and SOD2. Furthermore, survival analyses were assessed with a 122 retrospective human pancreatic cancer cohort. ResultsThe novel GPX4 inhibitor, RSL3, enhanced the effect of FOLFIRINOX by inducing ROS accumulation that triggered ferroptosis and apoptosis in vitro and a significant tumor shrinkage in vivo in those high ROS levels tumor cells. In contrast, SOD2 overexpression conferred resistance. Furthermore, high GPX4 and ROS expression levels were associated with shorter survival, while elevated SOD2 levels showed a subgroup with better prognosis in our cohort of 122 human pancreatic cancer cases. Thus, a novel molecular signature based on a GPX4-high/SOD2-low profile may help detect patients with the poorest clinical outcomes in pancreatic cancer. ConclusionsRedox homeostasis regulates susceptibility to ferroptosis and influences treatment efficacy in pancreatic ductal adenocarcinoma. Notably, sensitivity to ferroptosis was determined not only by GPX4 levels alone, but also by the balance between ROS accumulation and SOD2-mediated antioxidant buffering. These findings support a biomarker-guided approach to treatment stratification and provide a rationale for the clinical evaluation of redox-based therapeutic strategies in pancreatic ductal adenocarcinoma. Translational relevanceFerroptosis is a non-apoptotic form of cell death with emerging therapeutic potential in pancreatic ductal adenocarcinoma. This study demonstrates that combining FOLFIRINOX with the GPX4 inhibitor RSL3 selectively induces ferroptosis in tumors with high ROS levels, both in vitro and in vivo, without increasing toxicity. Notably, sensitivity to ferroptosis is not determined by GPX4 levels alone, but rather by the tumors capacity to tolerate oxidative stress, shaped by ROS accumulation and compensatory SOD2 expression. In our clinical cohort, high GPX4 and elevated ROS levels correlate with poor prognosis, whereas high SOD2 expression identifies a favorable subgroup. These findings establish redox signaling as a clinically relevant variable for defining novel molecular subtypes with prognostic significance and support the use of redox biomarkers for patient stratification in pancreatic ductal adenocarcinoma. This work provides a strong rationale for the clinical evaluation of ferroptosis-inducing agents in combination with standard chemotherapy in phase I trials, guided by tumor redox profiling to enhance therapeutic precision.

cancer biology↗

bioRxiv2025

Metabolic buffering suppresses phenotype switching in cancer

The impact of the microenvironment on epigenetically plastic cancer cells underpins phenotypic heterogeneity, a major cause of metastatic dissemination and therapy resistance that together represent the primary cause of cancer-related death. Nutrient limitation is a key microenvironmental stress that can cause a phenotypic transition from proliferation to invasion via activation of the integrated stress response. However, whether and how the capacity to store and mobilize nutrients impacts phenotype-switching through metabolic buffering remains unknown. Here, using melanoma as a model, we reveal that the ability to accumulate and mobilize glycogen, that buffers glucose availability, plays a key role in phenotypic transitions in melanoma. While proliferative phenotype cells exhibit high levels of glycogen, invasion is marked by low glycogen levels. Significantly, an inability to store and metabolize glycogen leads to phenotype instability and a switch to invasion. Accordingly, glycogen levels inversely correlate with Clark levels in primary melanomas, with low expression of the glycogen phosphorylases PYGB/L and phosphoglucomutase 1 (PGM1) being associated with worse overall survival. The importance of metabolic buffering in suppressing phenotypic transitions likely extrapolates to other cancer types. HighlightsO_LIMelanoma phenotypes are distinguished by their ability to store and mobilize glycogen. C_LIO_LIProliferative MITFHigh melanoma cells store glycogen to improve survival under stressful conditions. C_LIO_LIInhibition of glycogen degradation impairs proliferation in MITFHigh melanoma cells. C_LIO_LILack of PGM1 drives invasion and metastatic dissemination. C_LI

cancer biology↗

bioRxiv2025

c-Rel drives pancreatic cancer metastasis through Fibronectin-Integrin signaling-induced isolation stress resistance and EMT activation

Pancreatic ductal adenocarcinoma remains one of the deadliest malignancies, with limited treatment options and a high recurrence rate. Recurrence happens often with metastasis, for which cancer cells must adapt to isolation stress to successfully colonize distant organs. While the fibronectin-integrin axis has been implicated in this adaptation, its regulatory mechanisms require further elaboration. Here, we identify c-Rel as an oncogenic driver in PDAC, promoting epithelial-to-mesenchymal transition (EMT) plasticity, extracellular matrix (ECM) remodeling, and resistance to isolation stress. Mechanistically, c-Rel directly regulates fibronectin (Fn1) and CD61 (itgb3) transcription, enhancing cellular plasticity and survival under anchorage-independent conditions. Fibronectin is not essential for EMT, but its absence significantly impairs metastatic colonization, highlighting a tumor-autonomous role for FN1 in isolation stress adaptation. These findings establish c-Rel as a key regulator of PDAC metastasis by controlling circulating tumor cell (CTC) niche and survival, suggesting that targeting the c-Rel-fibronectin-integrin axis could provide new therapeutic strategies to mitigate disease progression and recurrence.

cancer biology↗

bioRxiv2024

SIRT1 mediates the antagonism of Wnt/β-catenin pathway by vitamin D in colon carcinoma cells.

Cancer initiation and progression result from both genetic alterations and epigenetic reprograming caused by environmental or endogenous factors which can lead to aberrant cell signalling. Most colorectal cancers (CRC) are linked to the abnormal activation of the Wnt/ {beta}-catenin pathway, whose key feature is the accumulation of acetylated {beta}-catenin protein within the nucleus of colon epithelial cells. Nuclear {beta}- catenin acts as a transcriptional co-activator that alters the expression of many target genes involved in cell proliferation and invasion. The most active vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol) can antagonize the over-activated Wnt/ {beta}-catenin pathway via binding to its high affinity receptor VDR. Here, we show that the activation of the SIRT1 deacetylase by 1,25(OH)2D3-bound VDR promotes deacetylation and nuclear exclusion of {beta}-catenin and, consequently, the downregulation of its pro-tumorigenic target genes and the inhibition of human colon carcinoma cell proliferation. Notably, orthogonal SIRT1 activation systematically drives nuclear exclusion of {beta}-catenin, highlighting the key role of SIRT1 in CRC. Since nuclear localization of {beta}-catenin is a critical driver of CRC initiation and progression that requires its acetylation, our results provide a mechanistic basis for the epidemiological evidence linking vitamin D deficiency and increased CRC risk and mortality.

cancer biology↗

bioRxiv2023

Vitamin D induces SIRT1 activation through K610 deacetylation in colon cancer

Posttranslational modifications of epigenetic modifiers provide a flexible and timely mechanism for rapid adaptations to the dynamic environment of cancer cells. SIRT1 is an NAD+-dependent epigenetic modifier whose activity is classically associated with healthy aging and longevity, but its function in cancer is not well understood. Here, we reveal that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol), the active metabolite of vitamin D (VD), promotes SIRT1 activation through auto-deacetylation in human colon carcinoma cells, and identify lysine 610 as an essential driver of SIRT1 activity. Remarkably, our data show that the post-translational control of SIRT1 activity mediates the antiproliferative action of 1,25(OH)2D3. This effect is reproduced by the SIRT1 activator SRT1720, suggesting that SIRT1 activators may offer new therapeutic possibilities for colon cancer patients who are VD deficient or unresponsive. Moreover, this might be extrapolated to inflammation and other VD deficiency-associated and highly prevalent diseases in which SIRT1 plays a prominent role.

cancer biology↗