Biology subjects

Coulouarn, C.

Publications and source records attributed to Coulouarn, C..

3 recordsLinked to original sources

bioRxiv2023

The hepatocyte Epidermal Growth Factor Receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche

Background & AimsLiver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of profibrotic factors are not well characterized. The Epidermal Growth Factor Receptor (EGFR) signaling in hepatocytes is essential for the regenerative process of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Approach & ResultsOur group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes ({Delta}EGFR mice). Here, we have analyzed the response of WT and {Delta}EGFR mice to chronic treatment with CCl4. Resultsindicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated {Delta}EGFR mice when compared to WT mice, coinciding with a faster resolution of the fibrotic process and an ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable change in the population of M2 macrophages, more related to fibrosis resolution, as well as an increase in the population of lymphocytes related to eradication of the damage. Transcriptomic analysis of hepatocytes and secretome studies from extracellular media in in vitro studies allowed to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-inflammatory and pro-fibrotic mediators. ConclusionsOur results support a pro-inflammatory and pro-fibrogenic role for the hepatocyte EGFR pathway during chronic liver damage.

pathology↗

bioRxiv2023

Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells

Non-small cell lung cancers (NSCLCs) treated with tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) almost invariably relapse in the long term, due to the emergence of subpopulations of resistant cells. Here we show that the lack of sensitivity of these cells to EGFR-TKIs constitutes a vulnerability that can be potentially targeted. Through a DNA barcoding approach, we demonstrate that the clinically approved drug sorafenib specifically abolishes the selective advantage of EGFR-TKI-resistant cells, while preserving the response of EGFR-TKI-sensitive cells, thus resulting in overall inhibition of clonal evolution within the tumor cell mass population. Sorafenib is active against multiple mechanisms of resistance/tolerance to EGFR-TKIs and its effects depend on early inhibition of MAPK interacting kinase (MNK) activity and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and later down-regulation of MCL1 and EGFR. Using several xenograft and allograft models to recapitulate different mechanisms and kinetics of acquired resistance, we show that the sorafenib-EGFR-TKI combination can substantially delay tumor growth and promote the recruitment of inflammatory cells. Together, our findings indicate that sorafenib can substantially prolong the response to EGFR-TKIs by targeting NSCLC capacity to adapt to treatment through the emergence of resistant cells.

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↗