Biology subjects

Chatziioannou, A.

Publications and source records attributed to Chatziioannou, A..

7 recordsLinked to original sources

bioRxiv2025

IRE1 activity regulates tumour and microenvironment cell lineage states while stratifying localised and metastatic prostate cancer.

Prostate cancer (PCa) is an androgen receptor (AR) driven, high-incidence disease significantly contributing to cancer mortality. PCa is in need of better risk stratification at diagnosis and treatment outcomes in patients at high risk of metastasis. The unfolded protein response (UPR) is an AR-dependent process. However, the impact of the UPR transducer IRE1 on AR-dependent biology and treatment resistance has not been defined. We use diverse pre-clinical models of stress response to describe IRE1 activity impact on multiple disease stages and demonstrate its involvement with poor prognosis (RB1 loss), and cell lineage determination (club phenotypes). Integrating clinical transcriptomic datasets, we chart IRE1 activity throughout PCa evolution by developing a PCa-specific, IRE1 activity gene set (IRE1_18) reflecting both tumoral and micro-environmental niches. IRE1_18 can determine tumoral identity, inform androgen deprivation treatment suitability, prognosticate localised and metastatic disease independently from AR activity, and guide IRE1 modulation as a novel combination therapeutic. Graphical Abstract created using Biorender.com O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/643042v3_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@18edd6aorg.highwire.dtl.DTLVardef@6a759eorg.highwire.dtl.DTLVardef@14ff3fborg.highwire.dtl.DTLVardef@1ae77d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Genomic characteristics and clinical significance of CD56+ Circulating Tumor Cells in Small Cell Lung Carcinoma

IntroductionCirculating Tumor Cells (CTC) have been studied in various solid tumors but clinical utility of CTC in Small Cell Lung Cancer (SCLC) remains unclear. The aim of the CTC-CPC study was to develop an EpCAM-independent CTC isolation method allowing isolation of a broader range of living CTC from SCLC and decipher their genomic and biological characteristics. Patients and methodsCTC-CPC is a monocentric prospective non-interventional study including treatment-naive newly diagnosed SCLC. CD56+CTC were isolated from whole blood samples, at diagnosis and relapse after first-line treatment and submitted to Whole-exome-sequencing (WES). ResultsPhenotypic study confirms tumor lineage and tumorigenic properties of isolated cells for the 4 patients analyzed with WES. WES of CD56+CTC and matched tumor biopsy reveal genomic alteration frequently impaired in SCLC. At diagnosis CD56+CTC were characterized by a high mutation load, a distinct mutational profile and a unique genomic, compared to match tumors biopsies. In addition to classical pathways altered in SCLC, we found new biological processes specifically affected in CD56+CTC at diagnosis. High numeration of CD56+CTC (>7/ml) at diagnosis was associated with ES-SCLC. Comparing CD56+CTC isolated at diagnosis and relapse, we identify differentially altered oncogenic pathways (e.g. DLL3 or MAPK pathway). ConclusionsWe report a versatile method of CD56+CTC detection in SCLC. Numeration of CD56+CTC at diagnosis is correlated with disease extension. Isolated CD56+CTC are tumorigenic and a distinct mutational profile. We report a minimal gene set as a unique signature of CD56+CTC and identify new affected biological pathways enriched in EpCAM-independent isolated CTC in SCLC.

cancer biology↗

bioRxiv2020

Protein homeostasis imprinting across evolution

Protein homeostasis (a.k.a. proteostasis) is associated with the primary functions of life, and therefore with evolution. However, it is unclear how the cellular proteostasis machines have evolved to adjust the protein biogenesis needs to environmental constraints. Herein, we describe a novel computational approach, based on semantic network analysis, to evaluate proteostasis differentiation during evolution. We show that the molecular components of the proteostasis network (PN) are reliable metrics to deconvolute the life forms into Archaea, Bacteria and Eukarya and to assess the evolution rates among species. Topological properties of semantic graphs were used as new criteria to evaluate PN complexity of 93 Eukarya, 250 Bacteria and 62 Archaea, thus representing a novel strategy for taxonomic classification. This functional analysis provides information about species divergence and pointed towards taxonomic clades that evolved faster than others. Kingdom-specific PN were identified, suggesting that PN complexity correlates evolution. Through the analysis of gene conservation, we found that the gains or losses that occurred throughout PN evolution revealed a dichotomy within both the PN conserved modules and within kingdom-specific modules. Since the PN is implicated in cell fitness, aging and disease onset, it could be used as a new metric to tackle mechanisms underlying gain-of-functions, and their biological ramifications.

bioinformatics↗

bioRxiv2020

Stromal NRG1 in luminal breast cancer defines pro-fibrotic and migratory cancer-associated fibroblasts

HER3 is highly expressed in luminal breast cancer subtypes. Its activation by NRG1 promotes activation of AKT and ERK1/2, contributing to tumour progression and therapy resistance. HER3-targeting agents that block this activation, are currently under phase 1/2 clinical studies, and although they have shown favorable tolerability, their activity as a single agent has proven to be limited. Here we show that phosphorylation and activation of HER3 in luminal breast cancer cells occurs in a paracrine manner and is mediated by NRG1 expressed by cancer-associated fibroblasts (CAFs). Moreover, we uncover an autocrine role of NRG1 in CAFs. This occurs independently of HER3 and results in the induction of a strong migratory and pro-fibrotic phenotype, describing a subset of CAFs with elevated expression of NRG1 and an associated transcriptomic profile that determines their functional properties. Finally, we identified Hyaluronan Synthase 2 (HAS2), a targetable molecule strongly correlated with NRG1, as an attractive player supporting NRG1 - autocrine signaling in CAFs.

cancer biology↗

bioRxiv2019

Constitutive IRE1α signaling maintains glioblastoma cell differentiation

Endoplasmic Reticulum (ER) proteostasis control and the Unfolded Protein Response (UPRER) have been shown to contribute to tumor development and aggressiveness. As such, the UPRER sensor IRE1 (referred to as IRE1 hereafter) is a major regulator of glioblastoma (GBM) development and is an appealing therapeutic target. To document IRE1 suitability as an antineoplastic pharmacological target, we investigated how this protein contributed to GBM cell reprogramming, a property involved in treatment resistance and disease recurrence. Probing the IRE1 activity molecular signature on transcriptome datasets of human tumors, showed that high IRE1 activity correlated with low expression of the main GBM stemness transcription factors SOX2, SALL2, POU3F2 and OLIG2. Henceforth, this phenotype was pharmacologically and genetically recapitulated in immortalized and primary GBM cell lines as well as in mouse models. We demonstrated that constitutive activation of the IRE1/XBP1/miR148a signaling axis repressed the expression of SOX2 and led to maintenance of a differentiation phenotype in GBM cells. Our results describe a novel role for IRE1 signaling in maintaining differentiated tumor cell state and highlight opportunities of informed IRE1 modulation utility in GBM therapy.

cancer biology↗

bioRxiv2019

IRE1-UBE2D3 signaling controls the recruitment of myeloid cells to glioblastoma.

Tumor cells are exposed to intrinsic and environmental challenges that trigger endoplasmic reticulum (ER) homeostasis alteration, in turn leading to ER stress. To cope with this, tumor cells engage an adaptive signaling pathway, the unfolded protein response (UPR) thus promoting the acquisition of malignant features. As such, glioblastoma multiforme (GBM), the most aggressive primary brain tumors, exhibit constitutive UPR signals to sustain growth. Herein, we showed that signaling elicited by one of the UPR sensors, IRE1, promotes GBM tumor invasion, angiogenesis and infiltration by macrophages. Hence, high IRE1 activity in tumors predicts worse outcome. We further dissect IRE1-dependent mechanisms that shape the brain tumor immune microenvironment towards myeloid cells. We identify an IRE1-dependent signaling pathway that directly controls the expression/release of proinflammatory chemokines (CXCL2, IL6, IL8) leading to tumor cell-mediated chemoattraction of neutrophils and macrophages. This pathway requires XBP1 non-conventional mRNA splicing and XBP1s-dependent expression of the E2 ubiquitin enzyme UBE2D3. The latter contributes to the degradation of the NF{kappa}B inhibitor I{kappa}B, leading to the up-regulation of proinflammatory chemokines. Our work identifies a novel IRE1/UBE2D3 proinflammatory signaling axis instrumental to pro-tumoral immune regulation of GBM.

cancer biology↗

bioRxiv2018

Qualitative modeling of signaling networks in replicative senescence by selecting optimal node and arc sets

Signaling networks are an important tool of modern systems biology and drug development. Here, we present a new methodology to qualitatively model signaling networks by combining experimental data and prior knowledge about protein connectivity. Unlike other methods, our approach does not focus solely on selecting which reactions are involved but also on whether a protein is present. This allows the user to model more complicated experiments and incorporate more knowledge into the model. To demonstrate the capabilities of our method we compared the signaling networks of young and replicative senescent human primary HFL-1 fibroblasts, whose differences are expected to be due mainly to changes in the expression of the proteins rather than the reactions involved. The resulting networks indicate that, compared to young cells, aged cells are not as responsive to insulin stimulation and activate pathways that establish and maintain senescence.\n\nAuthor summaryCells have developed a complex network of biochemical reactions to monitor their environment and react to changes. Although multiple pathways, tuned to identify specific stimuli, have been discovered, it is generally understood that the signaling process typically involves multiple pathways and is context depended. Consequently, reconstructing the signaling network utilized by cells at any given moment is not a trivial task. In this article, we report on a novel logic-based method for identifying signaling network by combining experimental data with prior knowledge about the connectivity of the involved proteins. Unlike other methods proposed so far, our method uses data to evaluate the presence or absence of reactions and proteins alike. We reconstructed and compared the signaling network of human primary HFL-1 fibroblasts as they undergo replicative senescence in the presence of 6 different stimuli. The resulting networks indicate that, compared to young cells, senescent cells are not responsive to insulin stimulation and activate pathways that are known to establish and maintain senescence.

systems biology↗