Biology subjects

Joffre, C.

Publications and source records attributed to Joffre, C..

9 recordsLinked to original sources

bioRxiv2026

A PTBP1-CDC42 splicing axis regulates leukemia growth and venetoclax sensitivity in acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by high rates of relapse and poor outcomes, especially in elderly or unfit patients, who cannot tolerate intensive chemotherapy. While the BCL2 inhibitor venetoclax has improved initial responses in this high-risk population, relapses remain nearly universal, highlighting the need for novel therapeutic strategies. Here, we identify the RNA-binding protein PTBP1 as a critical dependency in AML. PTBP1 depletion impairs leukemic growth in vitro and in vivo, and is associated with widespread splicing alterations and global disruption of protein synthesis. Integrative transcriptomic and iCLIP analyses reveal that PTBP1 orchestrates a splicing program centered on Rho GTPase signaling, with CDC42 as a key downstream effector. Mechanistically, PTBP1 loss triggers a splicing switch from CDC42-v1 to CDC42-v2, leading to reduced GTPase activity and impaired protein synthesis. Pharmacological inhibition of CDC42 selectively induces cytotoxicity in AML cells, while sparing healthy hematopoietic cells. Importantly, CDC42 inhibition markedly enhances venetoclax anti-leukemic efficacy. These findings establish PTBP1 as a critical regulator of AML cell fitness and identify a clinically actionable therapeutic combination that exploits AML dependency on PTBP1-CDC42 signaling to enhance the efficacy of venetoclax-based regimens.

cancer biology↗

bioRxiv2026

Low-molecular-weight Ulva lacinulata extract exhibiting anti-inflammatory and pro-autophagic activities in RAW 264.7 macrophages: a promising candidate for the development of active ingredients targeting low-grade inflammation

Marine macroalgae are valuable sources of bioactive compounds. In this study, we thus investigated the chemical composition and biological activity of an extract from the green seaweed Ulva lacinulata, composed of small bioactive compounds. Comprehensive compositional analyses and high-resolution mass spectrometry revealed its diverse molecular profile composed in particular of peptides/amino acid derivatives, saccharides, low-chain fatty diacids, oxylipins and minerals. Its anti-inflammatory activity was assessed after 6 h pre-treatment in LPS-stimulated cultured RAW 264.7 macrophages, showing that it significantly and dose-dependently reduced the expression and/or secretion of pro-inflammatory cytokines such as TNF- and IL-6, and targeted the NF-{kappa}B signaling cascade. It modulated the SIRT1-AMPK signaling axis and increased the LC3-II/LC3-I ratio, supporting the activation of a controlled autophagic response. This work highlighted the potential of this marine-derived extract as a safe and effective functional ingredient for the development of functional food and/or dietary supplements targeting chronic low-grade inflammation.

biochemistry↗

bioRxiv2026

Loss of p27Kip1 causes metabolic reprogramming and is sufficient to induce a Warburg effect and glutamine addiction in untransformed cells

The metabolic needs of a cell are tightly linked to its proliferative state and increasing evidence indicate an extensive bidirectional crosstalk between metabolic pathways and cell cycle regulators. In cancer cells, metabolism is reprogrammed to couple energetic needs and relentless proliferation. The cyclin/CDK inhibitor p27Kip1 (p27) is frequently inactivated in cancers. p27 is also involved in multiple cellular processes, including transcriptional regulation or autophagy induction. Herein, we investigated the effect of p27 loss on cell metabolism. The knockout of p27 in immortalized mouse fibroblasts increases glucose uptake and glycolysis, while decreasing mitochondrial ATP production, consistent with induction of a Warburg effect, and this was accompanied by an increased glutamine dependency to feed the TCA cycle. Our data suggest that p27 loss causes this phenotype through extensive transcriptional remodeling of metabolic gene expression. Importantly, p27 silencing in human retinal RPE1-hTERT cells was sufficient to induce a Warburg effect. Together, these results reveal a new function of p27 in regulating energy metabolism and that loss of p27 expression is sufficient to induce metabolic reprogramming and a Warburg effect, suggesting that p27 inactivation in cancer cells not only results in the loss of cell cycle inhibition but also enables the metabolic rewiring needed for increased proliferation.

cell biology↗

bioRxiv2025

Maternal n-3 PUFA deficiency alters brain fatty acid and oxylipin profiles across perinatal development in offspring

Long-chain polyunsaturated fatty acids (LC-PUFAs), particularly arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), are essential for optimal neurodevelopment through their effect on neuronal proliferation, neurite outgrowth and synaptogenesis. Emerging evidence highlights that brain PUFAs are metabolized in oxylipins, the bioactive oxidized PUFA metabolites known to regulate inflammatory processes. Recent data highlighted that both PUFA and oxylipin profiles are modulated in the adult male brain by dietary PUFA content. However, little is known on the impact of maternal dietary n-3 PUFA intake during the perinatal period and the neurodevelopmental profile of brain fatty acids and associated oxylipins in offspring, and whether these effects differ between sexes. To address this question, we first measured fatty acid levels in the placenta and embryonic brain of male and female offspring of mothers fed a sufficient or deficient diet in n-3 PUFAs at embryonic day (E)17.5. Then, fatty acids and oxylipins were measured at different post-natal stages, in the brain at P0 and P7, and in the hippocampus at P14 and P21, in both male and female offspring. Our results show that maternal n-3 PUFA dietary deficiency alters fatty acid profiles as early as E17.5 in both the placenta and the brain. Furthermore, dietary intervention affects both fatty acid and oxylipin profiles throughout postnatal brain development, with notable sex-specific differences. These findings underscore the critical importance of adequate maternal n-3 PUFA intake during the perinatal period for maintaining an optimal PUFA and oxylipin profiles, with potential implications for fetal and postnatal brain development.

neuroscience↗

bioRxiv2025

Autophagy driven by VPS34 enables differentiated cell plasticity and cancer initiation

Differentiated cell plasticity and autophagy are fundamental mechanisms of tissue repair. To investigate their integration to maintain tissue homeostasis, we developed a unique model in which VPS34, the highly conserved class III PI3K that promotes autophagic flux, was inactivated in pancreatic exocrine cells, recognised study models. Using scRNAseq, we found that VPS34-null acinar cells evolved towards a transcriptional identity present at low levels in mouse and human pancreas. Functionally, it unexpectedly prevented transdifferentiation, chronic pancreatitis and precancer initiation triggered by stressors. Mechanistically, the newly differentiated cell state was less susceptible to cancer promotion by oncogenic KRAS, through reduced class I PI3K and increased lysosomal degradation of pro-inflammatory REG3A. This result opens the so far unreachable possibility of strategies for protection from environmentally induced cancer initiation.

pathology↗

bioRxiv2020

Translatome-based classification reveals a dual metabolic dependency of a new tumor subtype of pancreatic cancer.

Molecular profiling of Pancreatic Ductal Adenocarcinoma (PDA), based on transcriptomic analyses, identifies two main prognostic subtypes (basal-like and classical), but does not allow personalized first-line treatment. To date, tumors have not been profiled based on protein synthesis rates, yet the step of mRNA translation is highly deregulated in both PDA cancer cells and their microenvironment. Using a collection of twenty-seven pancreatic Patient-Derived Xenografts (PDX), we performed genome-wide analysis of translated mRNA (translatome). Unsupervised bioinformatics analysis revealed a new tumor subtype harboring a low protein synthesis rate, but associated with a robust translation of mRNAs encoding effectors of the integrated stress response (ISR), including the transcription factor ATF4. Functional characterization of the "ISR-activated" human cancer cells revealed a high resistance to drugs, low autophagic capacities, and importantly, metabolic impairments in the serine synthesis and transsulfuration pathways. Overall, our study highlights the strength of translatomic profiling on PDA, which here revealed an unforeseen drug-resistant cancer cell phenotype, whose auxotrophy to both serine and cysteine may be amenable to targeted therapy.

cancer biology↗

bioRxiv2020

Mitochondrial determinants of response and resistance to venetoclax plus cytarabine duplet therapy in acute myeloid leukemia

The development of resistance to conventional and targeted therapy represents a major clinical barrier in treatment of acute myeloid leukemia (AML). We show that the resistance to cytarabine (AraC) and its associated mitochondrial phenotype were reversed by genetic silencing or pharmacological inhibition of BCL2 in a caspase-dependent manner. BCL2-inhibitor venetoclax (VEN) enhancement of AraC efficacy was independent of differentiation phenotype, a characteristic of response to another combination of VEN with hypomethylating agents (HMA). Furthermore, transcriptional profiles of patients with low response to VEN+AraC mirrored those of low responders to VEN+HMA in clinical trials. OxPHOS was found to be a patient stratification marker predictive of effective response to VEN+AraC but not to VEN+AZA. Importantly, whereas three cell subpopulations specifically emerged in VEN+AraC residual disease and were characterized by distinct developmental and transcriptional programs largely driven by MITF, E2F4 and p53 regulons, they each encoded proteins involved in assembly of NADH dehydrogenase complex. Notably, treatment of VEN+AraC-persisting AML cells with an ETCI inhibitor significantly increased the time-to-relapse in vivo. These findings provide the scientific rationale for new clinical trials of VEN+AraC combinations, especially in patients relapsing or non-responsive to chemotherapy, or after failure of frontline VEN+HMA regimen.

cancer biology↗

bioRxiv2020

p27 regulates the autophagy-lysosomal pathway via the control of Ragulator and mTOR activity in amino acid deprived cells

Autophagy is a catabolic process whereby cytoplasmic components are degraded within lysosomes, allowing cells to maintain energy homeostasis during nutrient depletion. Several studies have shown that the CDK inhibitor p27Kip1 promotes starvation-induced autophagy. However, the underlying mechanism remains unknown. Here, we report that in amino acid deprived cells, p27 controls autophagy via an mTORC1-dependent mechanism. During prolonged amino acid starvation, a fraction of p27 is recruited to lysosomes where it interacts with LAMTOR1, a component of the Ragulator complex required for mTORC1 lysosomal localization and activation. p27 binding to LAMTOR1 prevents Ragulator assembly and function and subsequent mTORC1 activation, thereby promoting autophagy. Conversely, upon amino acid withdrawal, p27-/- cells exhibit elevated mTORC1 signaling, impaired lysosomal activity and autophagy, and resistance to apoptosis. This is associated with sequestration of TFEB in the cytoplasm, preventing the induction of lysosomal genes required for lysosomal function. Silencing of LAMTOR1 or mTOR inhibition restores autophagy and induces apoptosis in p27-/- cells. Together, these results reveal a direct, coordinated regulation between the cell cycle and cell growth machineries.

cell biology↗

bioRxiv2019

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

Omega-3 fatty acids (n-3 polyunsaturated fatty acids; n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in epidemiological studies, but the mechanisms by which a n-3 PUFA dietary imbalance affects CNS development are poorly understood. Active microglial engulfment of synaptic elements is an important process for normal brain development and altered synapse refinement is a hallmark of several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development. Our results show that maternal dietary n-3 PUFA deficiency increases microglial phagocytosis of synaptic elements in the developing hippocampus, through the activation of 12/15- lipoxygenase (LOX)/12-HETE signaling, which alters neuronal morphology and affects cognition in the postnatal offspring. While women of child bearing age are at higher risk of dietary n-3 PUFA deficiency, these findings provide new insights into the mechanisms linking maternal nutrition to neurodevelopmental disorders.\n\nOne Sentence SummaryLow maternal omega-3 fatty acids intake impairs microglia-mediated synaptic refinement via 12-HETE pathway in the developing brain.

neuroscience↗