Biology subjects

Louis, C.

Publications and source records attributed to Louis, C..

3 recordsLinked to original sources

bioRxiv2025

ZEB1 regulates BCL2 in cancer-associated fibroblasts to promote cholangiocarcinoma chemoresistance to gemcitabine and cisplatin

Intrahepatic cholangiocarcinoma (iCCA) is an agressive tumour from the biliary tree that is characterized by a prominent desmoplastic stroma mainly composed of cancer-associated fibroblasts (CAF) and a poor prognosis due to its late clinical presentation and the lack of effective non-surgical treatments. Current therapies still include chemotherapeutic combinations of gemcitabine and cisplatin for the majority of the patients showing poor results due the apparition of resistance. This situation led us to interrogate the potential role in the development of chemoresistance of ZEB1, an EMT-inducing transcription factor (EMT-TF) that we previously identified as a pro tumorigenic factor in tumour cells and CAF of iCCA. By analysing human CCA samples and sc-RNAseq public databases, we show here that ZEB1 is present in the tumour microenvironment of all iCCA patients tested and is prominently expressed by CAF. Using cellular models of CAF, we show that cells depleted for ZEB1 are more sensitive to gemcitabine and cisplatin, via a mechanism involving the regulation of the anti-apoptotic gene BCL2. Moreover, ZEB1 expressing CAF protect iCCA tumour cells against the toxicity of the chemotherapeutic drugs, an event that could be reversed by a BCL2 inhibitor venetoclax. Therefore, our results point to the use of BCL2 inhibitors to improve the efficacy of current chemotherapeutic regimens of gemcitabine and cisplatin in iCCA patients.

cancer biology↗

bioRxiv2022

TGFβ-induced long non-coding RNA LINC00313 activates Wnt signaling and promotes cholangiocarcinoma

Cholangiocarcinoma (CCA) is a poor prognosis liver cancer characterized by high aggressiveness and resistance to therapy. Long non-coding RNAs (lncRNAs) and signals imposed by oncogenic pathways, such as transforming growth factor {beta} (TGF{beta}), contribute to cholangiocarcinogenesis. Here, we identified LINC00313 lncRNA as a novel target of TGF{beta} signalling in CCA cells. TGF{beta} induced LINC00313 expression in a T{beta}RI/Smad-dependent manner. Gene expression and genome-wide chromatin accessibility profiling revealed that nuclear LINC00313 transcriptionally regulated genes involved in Wnt signalling, such as TCF7. LINC00313 gain-of-function enhanced TCF/LEF-dependent transcription, promoted colony formation in vitro and accelerated tumour growth in vivo. Genes associated with LINC00313 over-expression in human CCA were characterized by KRAS and TP53 mutations and reduced patients overall survival. Mechanistically, actin-like 6A (ACTL6A), a subunit of SWI/SNF chromatin remodelling complex, interacted with LINC00313 and impacted on TCF7 and SULF2 transcription. We propose a model whereby TGF{beta} induces LINC00313 in order to regulate expression of hallmark Wnt pathway genes, in co-operation with SWI/SNF. By modulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.

cancer biology↗

bioRxiv2020

STAT3 Serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression

Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor (TLR)-4 expressed on macrophages induces a robust pro-inflammatory response which has recently been shown to be dependent on metabolic reprogramming 1, 2, 3, 4. These innate metabolic changes have been compared to the Warburg effect (also known as aerobic glycolysis) described in tumour cells 5, 6. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming remain unknown. Here we show that TLR4 activation induces a signalling cascade recruiting TRAF6 and TBK-1, while TBK-1 phosphorylates STAT3 on S727. Using a genetically engineered mouse model incapable of undergoing STAT3 Ser727 phosphorylation, we show both ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, the production of the central immune-metabolite succinate and inflammatory cytokine production in a model of LPS-induced inflammation. Our study identifies non-canonical STAT3 activation as the crucial signalling intermediary for TLR4-induced glycolysis, macrophage metabolic reprogramming and inflammation.

immunology↗