Biology subjects

de Carcer, G.

Publications and source records attributed to de Carcer, G..

6 recordsLinked to original sources

bioRxiv2026

Matrix biophysical cues drive transient or prolonged breast cancer dormancy programmes

Breast cancer metastasis can emerge after disease-free periods through the reawakening of dormant disseminated cancer cells. Despite evidence that the extracellular matrix (ECM) modulates this phenomenon, biophysical cues regulating dormancy fate and therapeutic responses remain poorly understood. Here, we engineered stiffness-matched gelatin methacryloyl (GelMA) and alginate-based 3D matrices to disentangle matrix stiffness from adhesion and degradability and uncover their contributions to dormancy. Deep learning-based 3D segmentation revealed that adhesive and degradable matrices supported rounded and proliferative tumour masses, whereas inert matrices favoured single cell dormancy. Within inert matrices, stiffness further determined dormancy fate, with soft matrices activating SOX9-associated transient stem-like dormancy, while stiff matrices reduced cell volume, increased intracellular macromolecular crowding of proteins and induced NR2F1-associated prolonged dormancy marked by autophagy and cellular stress. Transiently dormant cells retrieved from soft matrices retained dormancy memory and failed to form tumours in chicken chorioallantoic membranes, demonstrating persistence of matrix-induced states after removal of biophysical cues. Moreover, patient-derived cells in soft inert matrices recapitulated transient dormant states and exhibited therapy resistance. We demonstrate that tuneable biophysical cues shape distinct dormancy states, linking matrix mechanics to dormancy regulation and therapeutic response.

bioengineering↗

bioRxiv2025

Cyclin Y Overexpression Drives a Fatal Metabolic Syndrome via Defective Glucose Homeostasis

Cyclin Y (CCNY) is a membrane-associated, non-canonical cyclin best known for regulating WNT/beta-catenin signaling via the recruitment of CDK14/16 protein kinases. Whereas its role in the activation of members of the atypical CDK14-18 subfamily is established, its function in systemic metabolism remains poorly defined. Here, we report that CCNY overexpression drives a fatal metabolic syndrome. Using a novel inducible knock-in mouse model, we demonstrate that CCNY overexpression causes severe cachexia and profound hypoglycemia, resulting in death of adult mice independent of tumor burden. While these mutant mice maintain normal food intake and hepatic synthetic function, they succumb to metabolic starving state. Proteomics reveals that CCNY interacts with and stabilizes Pyruvate Dehydrogenase Kinase 4 (PDK4), in agreement with defective pyruvate use at mitochondria and enforcing a Warburg-like shift to aerobic glycolysis. Phosphoproteomic analysis indicates activation of apoptotic pathways and defective phosphorylation of several enzymes critical for glycolysis and gluconeogenesis as well as amino acid metabolism in addition to other metabolic routes. Altogether, these data suggest that CCNY overexpression uncouples nutrient sensing from utilization, a finding with possible therapeutic implications in CCNY-high cancers with similar changes in metabolic pathways.

cell biology↗

bioRxiv2024

Osmotic Stress Influences Microtubule Drug Response Via WNK1 Kinase Signaling

Ion homeostasis is critical for numerous cellular processes, and disturbances in ionic balance underlie diverse pathological conditions, including cancer progression. Targeting ion homeostasis is even considered as a strategy to treat cancer. However, very little is known about how ion homeostasis may influence anticancer drug response. In a genome-wide CRISPR-Cas9 resistance drug screen, we identified and validated the master osmostress regulator WNK1 kinase as a modulator of the response to the mitotic drug rigosertib. Osmotic stress and WNK1 inactivation lead to an altered response not only to rigosertib treatment but also to other microtubule-related drugs, minimizing the prototypical mitotic arrest produced by these drugs. This effect is due to an alteration in microtubule stability and polymerization dynamics, likely maintained by fluctuations in intracellular molecular crowding upon WNK1 inactivation. This promotes resistance to microtubule depolymerizing drugs, and increased sensitivity to microtubule stabilizing drugs. In summary, our data proposes WNK1 osmoregulation activity as a biomarker for microtubule-associated chemotherapy response.

cancer biology↗

bioRxiv2024

The signaling axis CDK12-BRCA1 mediates dinaciclib associated radiosensitivity through p53-mediated cellular senescence.

Pan-CDK inhibitors are a new class of targeted therapies that can act on multiple CDKs, with dinaciclib being one of the most promising compounds. Although used as monotherapy, an interesting approach could be to combine it with radiotherapy. Here we show that dinaciclib increases radiosensitivity in some experimental models of lung and colon cancer (A549 or HCT 116) but not in others (H1299 or HT-29). Dinaciclib did not alter responses such as ATM signalling, apoptosis or cell cycle profiling after ionising radiation exposure that have been described for other CDK inhibitors. Mechanistically, inhibition of CDK12 by dinaciclib abolishes BRCA1 expression, which blocks homologous recombination (HR), leaving only the non-homologous end joining repair process (NHEJ), which ultimately promotes the induction of ionising radiation-associated cellular senescence in a p53-dependent manner, explaining the lack of effect observed in some experimental models. In conclusion, our report explains the molecular mechanism involved in this novel therapeutic effect of dinaciclib and provides a rationale for more selective and personalised chemo/radiotherapy treatment according to the genetic background of the tumour. Highlights[tpltrtarr] Dinaciclib is a radiosensitising agent in lung and colon cancer cell lines. [tpltrtarr]Dinaciclib promotes radiosensitivity by inhibiting CDK12 leading to a decrease in BRCA1 expression. [tpltrtarr]Lack of BRCA1 blocks homologous recombination response to DNA damage, enhancing ionising radiation-associated senescence in a p53-dependent fashion. [tpltrtarr]The combination of dinaciclib plus radiotherapy could be a novel treatment for tumours holding functional BRCA1 and p53 signalling.

cancer biology↗

bioRxiv2023

TPX2 expression promotes sensitivity to dasatinib in breast cancer by activating the YAP transcriptional signaling.

Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN-positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN-associated genes in an inducible manner. We find that the overexpression of TPX2 enhances sensitivity to the SRC inhibitor dasatinib due to activation of the YAP pathway. Furthermore, using breast cancer data from the TCGA and a cohort of cancer-derived patient samples, we find that both TPX2 expression and YAP activation are present in a significant percentage of cancer tumor samples, providing poor prognosis, being therefore putative biomarkers for dasatinib therapy.

cancer biology↗

bioRxiv2018

Plk1 overexpression suppresses tumor development by inducing chromosomal instability

Polo-like kinase 1 (Plk1) is a protein kinase currently considered as an attractive cancer target due to its critical role in the cell division cycle. Plk1 is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression does not favor cell proliferation but rather results in abnormal chromosome segregation and cytokinesis, leading to the formation of polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge during cytokinesis in a Plk1 kinase-dependent manner. In vivo, elevated levels of Plk1 markedly prevent the development of mammary gland tumors induced either by KrasG12D or Her2, in the presence of increased rates of chromosome instability. In patients, higher Plk1 expression levels are associated with significantly increased overall survival in breast cancer subtypes. These data suggest that, despite the therapeutic benefits of inhibiting Plk1 due to its essential role in tumor cell cycles, Plk1 overexpression has tumor suppressive properties by perturbing mitotic progression and cytokinesis.

cancer biology↗