Biology subjects

Doridot, L.

Publications and source records attributed to Doridot, L..

3 recordsLinked to original sources

bioRxiv2024

Convergent gene expression in epithelial cells illuminates the evolution of uterine receptivity

The epithelium of the uterine endometrium is the first maternal interface encountered by the embryo, and plays crucial roles in the maternal-embryonic crosstalk necessary to embryo implantation. Mechanisms of embryo implantation are highly variable between mammals: humans and mice have convergently evolved similar embryo implantation phenotypes, where the embryo embeds in the maternal mucosa, which differs from the ancestral mammalian and primate phenotypes. This phenomenon is thought to be partly controlled by maternal epithelial receptivity signals during the window of implantation. Here, we combined endometrial epithelial organoid models and single-cell transcriptomics to investigate how gene expression has evolved in endometrial epithelial cells between human, non-human primates and mouse at key time points in the hormonal cycle. We discovered that many maternal genes involved in uterine receptivity and embryo implantation exhibit more similar expression patterns between human and mouse compared to macaque and marmoset. In particular, we show that the endometrial expression of LIF, a crucial actor of endometrial receptivity in both human and mouse, is likely an evolutionary convergence rather than a conserved feature as previously hypothesised.

evolutionary biology↗

bioRxiv2022

Mechanistic target of rapamycin (mTOR) regulates self-sustained quiescence, tumor indolence and late clinical metastasis in a Beclin-1-dependent manner.

Self-sustained quiescence (SSQ) has been characterized as a stable but reversible non-proliferative cellular state that limits the cloning of cultured cancer cells. By developing refined clonogenic assays, we showed here that cancer cells in SSQ can be selected with anticancer agents and that culture at low cell density induced SSQ in pancreas and prostate adenocarcinoma cells. Pre-culture of cells in 3D or their pretreatment with pharmacological inhibitors of mechanistic target of rapamycin (mTOR) synergize with low cell density for induction of SSQ in a Beclin-1-dependent manner. Dissociated pancreatic adenocarcinoma (PAAD) cells rendered defective for SSQ by down-regulating Beclin-1 expression exhibit higher tumor growth rate when injected subcutaneously into mice. Conversely, dissociated PAAD cells in SSQ promote the formation of small indolent tumors that eventually transitioned to a rapid growth phase. Ex vivo clonogenic assays showed that up to 40% of clonogenic cancer cells enzymatically dissociated from resected fast-growing tumors could enter SSQ, suggesting that SSQ could significantly impact the proliferation of cancer cells that are naturally dispersed from tumors. Remarkably, the kinetics of clinical metastatic recurrence in 124 patients with pancreatic adenocarcinoma included in the TGCA-PAAD project could be predicted from Beclin-1 and Cyclin-A2 mRNA levels in their primary tumor, Cyclin A2 mRNA being a marker of both cell proliferation and mTOR complex 1 activity. Overall, our data show that SSQ is likely to promote the late development of clinical metastases and suggest that identifying new agents targeting cancer cells in SSQ could help improve patient survival.

cancer biology↗

bioRxiv2021

HGFAC is a ChREBP Regulated Hepatokine that Enhances Glucose and Lipid Homeostasis

Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, in part, through actions to activate hepatic PPAR{gamma} activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of an HGFAC-HGF-PPAR{gamma} signaling axis in the liver to preserve glucose and lipid homeostasis.

physiology↗