Biology subjects

Vandier, C.

Publications and source records attributed to Vandier, C..

5 recordsLinked to original sources

bioRxiv2024

Single Cell Calcium profiling for the discrimination of cancer cell lines.

Calcium (Ca2+) is an essential second messenger that controls numerous cellular functions. Characteristics of intracellular Ca2+ oscillations define Ca2+ signatures representatives of the phenotype of a cell. Oncogenic functions such as migration, proliferation or resistance to chemotherapy have been associated with aberrant Ca2+ fluxes. However, the identification of Ca2+ signatures representatives of the oncogenic properties of cancer cells remains to be addressed. To characterize oncogenic Ca2+ signatures, we proposed an unbiased scalable method that combines single cell calcium imaging with unsupervised and supervised machine learning tools. Here, we applied this method to investigate the heterogeneity of Ca 2+ signatures in 16 cancer cell lines and the remodeling of oncogenic Ca2+ signatures induced by acquired docetaxel resistance and in the course of the interaction of cancer cells with fibroblasts. Finally, our method demonstrates the potential of Ca2+ profiling for discriminating cancer cells and predict their phenotypic characteristics at single cell level, and provides a framework for researchers to investigate the remodeling of the Ca2+ signature during cancer development.

cancer biology↗

bioRxiv2023

Encoding of the colorectal cancer metabolic program through MICU2

The mitochondrial Ca2+ uniporter (MCU) plays crucial role in intramitochondrial Ca2+ uptake, allowing Ca2+-dependent activation of oxidative metabolism. In recent decades, the role of MCU pore-forming proteins has been highlighted in cancer. However, the contribution of MCU-associated regulatory proteins mitochondrial calcium uptake 1 and 2 (MICU1 and MICU2) to pathophysiological conditions has been poorly investigated. Here, we describe the role of MICU2 in cell proliferation and migration using in vitro and in vivo models of colorectal cancer (CRC). Transcriptomic analysis demonstrated an increase in MICU2 expression and the MICU2/MICU1 ratio in advanced CRC and CRC-derived metastases. We report that expression of MICU2 is necessary for mitochondrial Ca2+ uptake and quality of the mitochondrial network. Our data reveal the interplay between MICU2 and MICU1 in the metabolic flexibility between anaerobic glycolysis and OXPHOS. Overall, our study sheds light on the potential role of the MICUs in diseases associated with metabolic reprogramming. HighlightsO_LIMICU2 plays a pivotal role in the balance between anaerobic glycolysis and oxidative phosphorylation C_LIO_LIMICU2 stabilizes the mitochondrial network and endoplasmic reticulum-mitochondrial calcium flux C_LIO_LIMICU2 expression and the MICU2/MICU1 ratio control proliferation and metastasis formation in colorectal cancer C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/564893v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@6bb307org.highwire.dtl.DTLVardef@b6a966org.highwire.dtl.DTLVardef@2ba053org.highwire.dtl.DTLVardef@2ab691_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Chimeric protein EWS-FLI1 drives cell proliferation in Ewing Sarcoma via overexpression of KCNN1.

Ewing sarcoma (ES) is characterized by chimeric fusion proteins, which act as oncogenes. Over the last decade, patient survival has not increased, especially for high risk patients. Knowing that ion channels are studied for their implication in tumorigenesis, the aim of this work is to study the involvement of the SK1 potassium channels in ES. RNA-Seq analyses showed a high restricted expression of KCNN1, the gene encoding SK1, only in ES patients, and its expression is inversely correlated with patient survival. EWS-FLI1 silencing demonstrated the regulation of KCNN1 by these fusion proteins, which bind at GGAA microsatellites near KCNN1 promoter. In addition, KCNN1 has been shown to be involved in the regulation of ES cell proliferation, its silencing being associated with a slowing of the cell cycle. Finally, KCNN1 expression modulates membrane potential and calcium flux suggesting the role of calcium in KCNN1 driving cell proliferation. These results highlight that KCNN1 is a direct EWS-FLI1 and EWS-ERG target, and is involved in the regulation of ES cell proliferation, making it an interesting therapeutic target in ES.

cancer biology↗

bioRxiv2022

Curcumin and NCLX Inhibitors Share Anti-Tumoral Mechanisms in Microsatellite-Instability-Driven Colorectal Cancer

Colorectal cancer (CRC) is associated with high mortality worldwide and new targets are needed to overcome treatment resistance. Recent evidences highlight a role of the mitochondria calcium homeostasis in the development of CRC. In this context, we aimed to evaluate the role of the mitochondrial sodium-calcium-lithium exchanger (NCLX) and its targeting in CRC. We also identified curcumin as a new potential inhibitor of NCLX. In vitro, curcumin exerted strong anti-tumoral activity through its action on NCLX with mtCa2+ and reactive oxygen species overload associated with a mitochondrial membrane depolarization, leading to reduced ATP production and apoptosis through mitochondrial permeability transition pore opening concomitant with G2/M cell cycle arrest. NCLX inhibition with either CGP37157 (a benzodiazepine derivative), small interfering RNA-mediated knock-down or knockout approaches reproduced the effects of curcumin. Altered mitochondrial respiration, cellular aerobic glycolysis and endoplasmic reticulum-mitochondria membrane perturbations participated in these mechanisms. In a xenograft mouse model, NCLX inhibitors decreased CRC tumor growth. Both transcriptomic analysis of The Cancer Genome Atlas dataset and immunohistochemical analysis of tissue microarrays from 381 patients with microsatellite instability (MSI)-driven CRC demonstrated that higher NCLX expression was associated with MSI status and for the first time NCLX expression was significantly associated with recurrence-free survival in MSI CRC patients. Our findings provide strong evidence that blocking NCLX inhibits CRC in vitro and in vivo. We highlight a novel anti-tumoral mechanism of curcumin through its action on NCLX and mitochondria calcium overload that could benefit for therapeutic treatment of patients with MSI CRC.

cancer biology↗

bioRxiv2021

CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer

Androgen deprivation therapy (ADT) is the main treatment for advanced prostate cancer (PCa) but resistance results in progression to terminal castrate resistant PCa (CRPC), where there is an unmet therapeutic need. Aberrant intracellular calcium (Cai2+) is known to promote neoplastic transformation and treatment resistance. There is growing evidence that expression of voltage gated calcium channels (VGCC) is increased in cancer, particularly the CACNA1D/CaV1.3 in CRPC. The aim of this study was to investigate if increased CaV1.3 drives resistance to ADT and determine its associated impact on Cai2+ and cancer biology. Bioinformatic analysis revealed that CACNA1D gene expression is increased in ADT treated PCa patients regardless of TMPRSS2:ERG status. Corroborated in both in vivo LNCaP xenograft mouse and in vitro PCa cell line models which demonstrated a significant increase in CaV1.3 protein expression following ADT with bicalutamide. The expression was found to be a shortened 170kDA CaV1.3 isoform associated which failed to mediate calcium influx following membrane depolarisation. Instead, under ADT CaV1.3 mediated a rise in basal cytosolic calcium and an increase in store operated calcium entry (SOCE). This in turn drove both proliferation and survival of long-term ADT CRPC cells. Overall, this study demonstrates for the first time in PCa that increased SOCE through a novel CaV1.3 mechanism which represents a novel oncogenic switch that contributes to ADT resistance and promotes CRPC biology. Highlighting aberrant intracellular calcium in CRPC as a potential area for therapeutic development to improve patient outcomes.

cancer biology↗