Biology subjects

Guillermet-Guibert, J.

Publications and source records attributed to Guillermet-Guibert, J..

15 recordsLinked to original sources

bioRxiv2026

Diet modulates metabolic and hepatic responses to chronic pesticide mixture exposure in mice

Chronic exposure to pesticide mixtures through diet is common, yet their combined metabolic effects and interactions with dietary factors remain unclear. We identified four pesticides prevalent in human exposure (imazalil, thiabendazole, boscalid, lambda-cyhalothrin) and assessed their combined impacts on hepatic metabolism and metabolic homeostasis using human liver cells and male mice fed standard chow or western diets. We found that the pesticide mixture induced metabolic perturbations in human hepatocytes. In addition, the pesticide mixture altered hepatic gene expression in chow-fed mice and exacerbated western diet-induced glucose intolerance, fasting hyperglycemia, and insulin resistance without affecting body weight or liver steatosis. These findings reveal that dietary context influences the metabolic consequences of pesticide mixtures, highlighting the need to consider nutritional status when evaluating environmental contaminant risks. Our results suggest that pesticide mixtures at reference doses may contribute to metabolic dysregulation, particularly under obesogenic dietary conditions. Highlights- Four common pesticides in mixture disrupt metabolism in liver cells - Dietary exposure to this pesticide mixture alters hepatic gene expression in mice - The pesticide mixture exacerbates WD-induced disruptions in glucose homeostasis - Pesticides and diet interact in producing the metabolic effects of a pesticide mixture

pharmacology and toxicology↗

bioRxiv2025

Mutants of p53 sustain tumor growth under mechanical compression

ContextSolid tumors are subjected to mechanical stimuli arising from their growth in confined environments. Growth-induced pressure builds up in tumors such as pancreatic cancer and rises alongside the occurrence of genetic alterations during tumorigenesis. This study aims to understand the so far unknown relationship between genetic alterations and cancer cell behavior under compressive stress. ResultsUsing isogenic cell lines with engineered p53 mutations, we showed that the p53 background influences cell response to compression. Tumor growth under compression increased in cells harboring a mutated-truncated p53 form. This mutation blocked caspase 3 cleavage and promoted survival and growth through PI3K-AKT activation and dysregulation of c-FOS and FOSB transcription factors network. Mutated-truncated p53 cells displayed a unique behavior and heightened an activation state under compression. ConclusionMechanical compression and p53 mutations together drive tumor growth. p53 status could be a biomarker for predicting tumor adaptation to mechanical stress and efficiency of therapies targeting mechanosensitive pathways. TeaserMechanical compression and p53 mutations together enhance cancer cell survival and growth, driving solid tumor progression.

cancer biology↗

bioRxiv2025

Self-organization of tumor heterogeneity and plasticity

Phenotypic heterogeneity and plasticity drive tumor growth, metastasis, therapy resistance, and relapse. This heterogeneity is mainly interpreted as a response to external signals from the microenvironment. However, here we show that cancer cells also follow intrinsic self-organized programs that are sufficient to coordinate the spatiotemporal patterning of tumor cell states. By combining quantitative measurements in tumors and organoids with theoretical modeling, we reveal emergent mechanical gradients that orchestrate cell state transitions during colorectal tumor growth. Compression at the tumor center induces a transition from a fetal-like state into a cancer stem cell (CSC) state. The CSC compartment exhibits a characteristic size determined by tumor rheological properties. Once this size is surpassed, a translationally arrested apoptotic core emerges, triggering a shift from homogeneous proliferation to a hierarchical cell turnover. These findings uncover stereotyped programs of self-organization that likely cooperate with the microenvironment to shape tumor heterogeneity and plasticity.

cancer biology↗

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↗

bioRxiv2025

Proportional modulation of proliferation and motility under 2D compressive stress depends on mesenchymal phenotype

Tumor development is accompanied by strong physico-chemical modifications. Among them, compressive stress can emerge in both the epithelial and stromal compartments. Using a simple two-dimensional compression assay which consisted in placing an agarose weight on top of adherent cells, we studied the impact of compressive stress on cell proliferation and motility in different pancreatic cancer cell lines. We observed a proportional reduction of both proliferation and motility in all tested cell types, with genotypes displaying a more "mesenchymal" phenotype (high velocity-to-proliferation ratio) and others related to a more "epithelial" phenotype (low velocity-to-proliferation ratio). Moreover, "mesenchymal" cells seemed more sensitive to compression, a result that was further suggested by a TGF{beta}1 induction of epithelial-to-mesenchymal transition. Finally, we measured that the change in cell proliferation was associated with a change in intracellular macromolecular crowding, which could modulate a plethora of biochemical reactions. Our results together suggest a mechanism in which all biochemical reactions related to proliferation and motility can be modulated by a change in macromolecular crowding, itself depending on the phenotype, leading to differential sensitivity to pressure.

biophysics↗

bioRxiv2024

p110α-dependent hepatocyte signaling is critical for liver gene expression and its rewiring in MASLD

Insulin and other growth factors are key regulators of liver gene expression, including in metabolic diseases. Most of the phosphoinositide 3-kinase (PI3K) activity induced by insulin is dependent on PI3K. We used mice lacking p110, the catalytic subunit of PI3K, to investigate its role in the regulation of liver gene expression in health and in Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). The absence of hepatocyte PI3K signaling promoted glucose intolerance in lean mice and significantly regulated liver gene expression, including insulin-sensitive genes, in ad libitum feeding. Some of the defective regulation of gene expression in response to hepatocyte-restricted insulin receptor deletion was related to PI3K signaling. In addition, though PI3K deletion in hepatocytes promoted insulin resistance, it was protective against steatotic liver disease in diet-induced obesity. In the absence of hepatocyte PI3K, the effect of diet-induced obesity on liver gene expression was significantly altered, with changes in rhythmic gene expression in liver. Altogether, this study highlights the specific role of p110 in the control of liver gene expression in physiology and in the metabolic rewiring that occurs during MASLD.

cell biology↗

bioRxiv2023

PI3Kα activity in PHGDH-low pancreatic epithelial cells limits tissue proliferative regeneration in cancer promoting conditions

ObjectiveIncreased consumption of meat is an epidemiologically validated risk condition for pancreatic cancer development, but the underlying mechanisms and whether it is related to induction of epithelial cell plasticity are unknown. DesignExperimental protocol to test the influence of high consumption of meat was compared to pancreatic inflammation experimental models. To determine the molecular drivers promoting pancreatic cell plasticity, we compared transcriptomics data sets from human samples of pancreatic inflammation and pancreatic cancer (PDAC) prone to plasticity and validated in vivo, ex vivo and in vitro the main identified target. ResultsMeat-enriched diet promoted plasticity of pancreatic acinar cells, that transdifferentiated in duct-like cells, and presented PI3K activation. We identified a selective PI3K activation gene signature enriched with plasticity. In this signature, PHGDH, which encodes an enzyme responsible for amino acid serine synthesis, was differentially expressed. High level of PHGDH in acinar cells was necessary for the proliferative action of PI3K sustained by an increased maximal mitochondrial capacity and decreased cyclin-dependent inhibitor p27 level. PHGDH level was decreased in transdifferentiated acinar cells. In this context, active PI3K promoted cell plasticity but decreased the number of cycling cells. Both epithelial-restricted genetic inactivation of PI3K and full PI3K inhibition by pharmacological dosage reduced inflammation-induced tissue damage, while a pharmacological PI3K activator promoted PanIN precancer lesion development. ConclusionMeat-enriched diet promoted plasticity. Blockage of plasticity by PI3K inhibition provoked an increased rate of acinar cell proliferation that had a beneficial impact on the tissue microenvironment less prone to precancer lesion development. What is already known on this topicIt is now well accepted that inflammatory conditions predispose to pancreatic tumour development; increased consumption of red and processed meat is an epidemiologically validated risk condition, but the underlying mechanisms are unknown. What this study addsWe identify PI3K activation as a common molecular pathway activated by increased consumption of red and processed meat and by inflammatory condition to promote pancreatic plasticity and precancer lesion development. How this study might affect research, practice or policyAs we show that treatments with the clinically available PI3K inhibitor block pancreatic plasticity under inflammatory stress while maintaining pancreas mass and limiting inflammatory reaction damage, they may represent an efficient and safe preventive interception drug in patients at risk of developing pancreatic cancer. PI3K pro-cancer action is exacerbated by the loss of serine synthesis enzyme; hence, diets that alter amino acid synthesis should be tightly controlled in those patients.

pathology↗

bioRxiv2023

An easy-to-use microfluidic mechano-chemostat for tissues and organisms reveals that confined growth is accompanied with increased macromolecular crowding

Conventional culture conditions are oftentimes insufficient to study tissues, organisms, or 3D multicellular assemblies. They lack both dynamic chemical and mechanical control over the microenvironment. While specific microfluidic devices have been developed to address chemical control, they are often hard to use and do not allow the control of compressive forces. Here, we present a set of microfluidic devices which all rely on the use of sliding elements consisting of microfabricated rods that can be inserted inside a microfluidic device. Sliding elements enable the creation of reconfigurable sealed culture chambers for the study of whole organisms or model micro-tissues. By confining the micro-tissues, we studied the biophysical impact of growth-induced pressure and showed that this mechanical stress is associated with an increase in macromolecular crowding, shedding light on this understudied type of mechanical stress. Our mechano-chemostat is an easy-to-use microfluidic device that allows the long-term culture of biological samples and can be used to study both the impact of specific conditions as well as the consequences of mechanical compression.

biophysics↗

bioRxiv2023

The Loss of the E3 ubiquitin ligase TRIP12 inhibits Pancreatic Acinar Cell Plasticity and Tumor Cell Metastatic Capacity

Background & AimsAlthough specialized and dedicated to the production of digestive enzymes, pancreatic acinar cells harbor a high plasticity and are able to modify their identity. They undergo reversible acinar-to-ductal cell metaplasia (ADM) through epigenetic silencing of the acinar lineage gene program mainly controlled by PTF1a (Pancreas Transcription Factor 1a). ADM becomes irreversible in the presence of oncogenic Kras mutations and leads to the formation of preneoplastic lesions. We investigated the role of the E3 ubiquitin ligase Thyroid hormone Receptor Interacting Protein 12 (TRIP12), involved in PTF1a degradation, in pancreatic carcinogenesis. MethodsWe used genetically engineered mouse models of pancreas-selective Trip12 deletion, mutant Kras (G12D) and mutant Trp53 (R172H). We performed RNA sequencing analysis from acinar cells and cell lines derived from mice models tumors. We investigated the impact of TRIP12 deficiency on acute pancreatitis, tumor formation and metastasis development. ResultsTRIP12 is overexpressed in human pancreatic preneoplastic lesions and tumors. We show that a conditional deletion of TRIP12 in the pancreas during murine embryogenesis alters pancreas homeostasis and acinar cell genes expression patterns in adults. EGF induced-ADM is suppressed in TRIP12-depleted pancreatic acini. In vivo, a loss of TRIP12 prevents acini to develop ADM in response to pancreatic injury, the formation of Kras-induced pancreatic preneoplastic lesions, and impairs tumors and metastasis formation in the presence of mutated Trp53. TRIP12 is required for Claudin18.2 isoform expression in pancreatic tumors cells. ConclusionsOur study identifies TRIP12 as a novel regulator of acinar fate in the adult pancreas with an important dual role in pancreatic carcinogenesis, in initiation steps and in metastatic behavior of tumor cells. SynopsisThis study shows that Thyroid hormone Receptor Interacting Protein 12 plays an important dual role in the initiation steps and invasion of pancreatic carcinogenesis. Moreover, expression of TRIP12 switches on the expression of Claudin-18, a targetable biomarker of pancreatic tumors.

cancer 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

The biomechanical context influences the output signaling, independently of PIK3CA mutations in breast cancer cells.

ContextMechanical stresses, including compression, arise during cancer progression. In solid cancer, especially breast and pancreatic cancers, the rapid tumor growth and the environment remodeling explain their high intensity of compressive forces. However, the sensitivity of compressed cells to targeted therapies remains poorly known. ResultsIn breast and pancreatic cancer cells, pharmacological PI3K inactivation decreased cell number and induced apoptosis. These effects were accentuated when we applied 2D compression forces in mechanically responsive cells. Compression selectively induced overexpression of PI3K isoforms and PI3K/AKT pathway activation. Further, transcriptional effects of PI3K inhibition and compression converged to control the expression of an autophagy regulator, GABARAP, which level was inversely associated with PI3K inhibitor sensitivity under compression. Compression alone blocked autophagy flux in all tested cells, while inactivation of basal PI3K activity restored autophagy flux only in mechanically non-responsive compressed cells. ConclusionThis study provides direct evidence for the role of PI3K/AKT pathway in compression-induced mechanotransduction. PI3K inhibition promotes apoptosis or autophagy, explaining PI3K importance to control cancer cell survival under compression.

bioinformatics↗

bioRxiv2020

Phosphoproteomics identifies PI3K inhibitor-selective adaptive responses in pancreatic cancer cell therapy and resistance

The PI3K pathway is highly active in human cancers. The four class I isoforms of PI3K are activated by distinct mechanisms leading to a common downstream signaling. Their downstream redundancy is thought to be responsible for treatment failures of PI3K inhibitors. We challenged this concept, by mapping the differential phosphoproteome evolution in response to PI3K inhibitors with different isoform selectivity patterns in pancreatic cancer, a disease currently without effective therapy. In this cancer, the PI3K signal was shown to control cell proliferation. We compared the effects of LY294002 that inhibit with equal potency all class I isoenzymes and downstream mTOR with the action of inhibitors with higher isoform-selectivity towards PI3K, PI3K{beta} or PI3K{gamma} (namely A66, TGX-221 and AS-252424). A bioinformatics global pathway analysis of phosphoproteomics data allowed us to identify common and specific signals activated by PI3K inhibitors supported by the biological data. AS-252424 was the most effective treatment and induced apoptotic pathway activation as well as the highest changes in global phosphorylation-regulated cell signal. However, AS-252424 treatment induced re-activation of Akt, therefore decreasing the treatment outcome on cell survival. Reversely, AS-252424 and A66 combination treatment prevented p-Akt reactivation and led to synergistic action in cell lines and patient organoids. The combination of clinically approved -selective BYL-719 with {gamma}-selective IPI-549 was more efficient than single molecule treatment on xenograft growth. Mapping unique adaptive signaling responses to isoform-selective PI3K inhibition will help to design better combinative treatments that prevent the induction of selective compensatory signals. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/313833v3_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@32004eorg.highwire.dtl.DTLVardef@b22f25org.highwire.dtl.DTLVardef@352a98org.highwire.dtl.DTLVardef@7f97a1_HPS_FORMAT_FIGEXP M_FIG C_FIG SignificanceHalf of all human cancers show increased PI3K activity but the mutational pattern of the PI3K pathway is not sufficient to predict sensitivity to PI3K inhibitors. By identifying for the first time specific signaling induced by PI3K inhibitors with different isoform-selectivity patterns, we provide insight in how to handle heterogeneity of PI3K expression in tumor samples for the choice of available PI3K-targetting drugs. Our work provides a roadmap to target the PI3K pathway, balancing the use of isoform-selective PI3K inhibitors with personalized information extending beyond the specific mutational status.

cancer biology↗

bioRxiv2020

Pancreatic Cancer Intrinsic PI3Kα Activity accelerates Metastasis and rewires Macrophage Component

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micrometastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We researched a gene signature that could discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. Amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3K activation signature predict PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3K-selective inhibition prevented macro-metastatic evolution by inhibiting tumoural cell migratory behaviour independently of genetic alterations. We found that PI3K inhibition altered the quantity and the species composition of the lipid second messenger PIP3 produced, with selective reduction of C36:2 PI-3,4,5-P3. PI3K inactivation prevented the accumulation of protumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour-cell intrinsic PI3K therefore promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution. The paper explainedPROBLEM Pancreatic cancer is one of the most lethal solid cancers characterised by rapid progression after primary tumour detection by imaging. Key signalling events that specifically drives this rapid evolution into macro-metastatic disease are so far poorly understood. RESULT With two unbiased approaches to patient data analysis, higher PI3K pathway and more specifically higher PI3K activation signature can now be identified in the most aggressive pancreatic cancer primary tumours, that lead to earlier patient death. Our in vitro data showed that PI3K is a major positive regulator of tumour cell escape from the primary tumour: tumour-intrinsic PI3K activity enables actin cytoskeleton remodelling to escape the pancreatic tumour. We chose to use two preclinical models of pancreatic cancer to validate that PI3K is a target for delaying evolution of PDAC. The first one mimicked pancreatic patient micrometastatic disease that is undetected by echography and consisted in treating mice presenting echography detected primary tumours combined with increased circulating DNA as a blood biomarker of the most aggressive tumours. The second model consisted in studying the tumour cell implantation and their early proliferation in metastatic organ after injection in blood. We treated both preclinical models with a clinically relevant PI3K -selective inhibitor (BYL-719/Alpelisib), that is currently being tested in pancreatic cancer patients (without any patient selection). We found that PI3K activity drives evolution of micrometastatic disease towards macro-metastatic stage in both models: inhibition of PI3K delayed primary tumour and micro-metastasis evolution. Finally, PI3K activity increases protumoural characteristics in peritumoural immune cells via tumour cell-intrinsic cytokine production that could facilitate metastatic evolution. IMPACT Circulating tumour DNA represents a strong independent biomarker linked to relapse and poor survival in solid cancer patients. A clinical study in resected PDAC patients with micrometastatic disease characterised by high circulating tumoural DNA levels is needed to assess if PI3K-selective inhibitors significantly delay metastatic progression and death. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/307884v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@a5a8b4org.highwire.dtl.DTLVardef@1e6e18dorg.highwire.dtl.DTLVardef@e22859org.highwire.dtl.DTLVardef@1c7148b_HPS_FORMAT_FIGEXP M_FIG Pancreatic ductal adenocarcinoma requires tumour-intrinsic PI3K activity to accelerate inflammatory metastatic disease. Biorender illustration. C_FIG

cancer biology↗

bioRxiv2019

Nuclear upregulation of PI3K p110β correlates with increased rRNA transcription in endometrial cancer cells

Genes encoding for components of the phosphoinositide 3-kinase (PI3K) pathway are frequently mutated in cancer, including inactivating mutations of PTEN and activating mutations of PIK3CA, encoding the PI3K catalytic subunit p110. PIK3CB, encoding p110{beta}, is rarely mutated, but can contribute to tumourigenesis in some PTEN-deficient tumours. The underlying molecular mechanisms are however poorly understood. By analysing cell lines and annotated clinical samples, we have previously found that p110{beta} is highly expressed in endometrial cancer (EC) cell lines and that PIK3CB mRNA levels increase early in primary tumours correlating with lower survival. Selective inhibition of p110 and p110{beta} led to different effects on cell signalling and cell function, p110 activity being correlated to cell survival in PIK3CA mutant cells and p110{beta} with cell proliferation in PTEN-deficient cells. To understand the mechanisms governing the differential roles of these isoforms, we assessed their sub-cellular localisation. p110 was cytoplasmic whereas p110{beta} was both cytoplasmic and nuclear with increased levels in both compartments in cancer cells. Immunohistochemistry of p110{beta} in clinically annotated patient tumour sections revealed high nuclear/cytoplasmic staining ratio, which correlated significantly with higher grades. Consistently, the presence of high levels of p110{beta} in the nuclei of EC cells, correlated with high levels of its product phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) in the nucleus. Using immunofluorescence labelling, we observed both p110{beta} and PtdIns(3,4,5)P3 in the nucleoli of EC cell lines. The production of nucleolar PtdIns(3,4,5)P3 was dependent upon p110{beta} activity. EC cells with high levels of nuclear PtdIns(3,4,5)P3 and p110{beta} showed elevated nucleolar activity as assessed by the increase in 47S pre-rRNA transcriptional levels in a p110{beta}-dependent manner. Altogether, these results present a nucleolar role for the PI3K pathway that may contribute to tumour progression in endometrial cancer.

molecular biology↗

bioRxiv2019

The lipid kinase PI3Kα is required for aggregation and survival of intraperitoneal cancer cells.

AO_SCPLOWBSTRACTC_SCPLOWBreast, ovarian, digestive and lung adenocarcinomas are often associated with the accumulation of malignant cells in serous cavities. As PI3K is one of the most mutated pathways in cancer, we investigated the importance of oncogenic PI3K in this process. We analyzed tumor cell organization in ascites from carcinomas at diagnosis. In some malignant ascites, tumor cells grew as adhesive coherent masses. Ex-vivo patient-derived cell cultures with the addition of mesenchymal stem cells, as a model of tumoral stroma, favored the compaction of tumorospheres. Ascites-derived ovarian cancer cell lines frequently harbored PIK3CA mutations coexisting with other mutations. PI3K promoted the formation and maintenance of multicellular adhesive PIK3CA-mutant spheroids, promoting cell survival. Cultures in 3D conditions as opposed to cultures in cell monolayers increased chemotherapy resistance, which was overcome by PI3K inhibition. We identified a signaling pathway of interest for the treatment of cancer cells disseminated in serous cavities, limiting cancer progression. Graphical abstractSchematic representation of PI3K involvement in tumor cell aggregates from ascites. 1) Known involvement of PI3K in primary ovarian tumors. 2) PI3K participates in tumorosphere formation within the peritoneum (treatment with PI3K inhibitors causes a delay in the formation of clusters). 3) PI3K participates in the maintenance of tumorospheres and in resistance to conventional treatment for peritoneal carcinomatosis. PI3K is a target to prevent transcoelomic dissemination and maintenance of tumorospheres in patients with ovarian cancer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/777649v3_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@15d4fa2org.highwire.dtl.DTLVardef@1175601org.highwire.dtl.DTLVardef@10f801dorg.highwire.dtl.DTLVardef@a41771_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗