Biology subjects

Bertucci, F.

Publications and source records attributed to Bertucci, F..

16 recordsLinked to original sources

bioRxiv2026

The atypical cadherin CELSR2 regulates distinct epithelial-mesenchymal states and oxidative phosphorylation in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by marked intratumoral heterogeneity, which contributes to metastatic dissemination, therapeutic resistance, and poor clinical outcome. Epithelial-mesenchymal plasticity is a major contributor to this heterogeneity. Identifying the molecular regulators governing epithelial-mesenchymal plasticity is therefore essential to understanding how distinct tumor cell populations arise and fuel TNBC progression. Here, we identify the adhesion G protein-coupled receptor CELSR2 as an independent poor-prognosis marker and regulator of epithelial-mesenchymal plasticity in TNBC. Spatial transcriptomic analyses revealed segregation of CELSR2high tumor cells within the epithelial tumor core and CELSR2low tumor cells at the invasive front. In line with the latter observation, CELSR2 expression decreases during EMT and its loss promotes acquisition of a hybrid epithelial-mesenchymal state. CELSR2high tumor cells display a CREB-associated oxidative phosphorylation (OXPHOS) program and promote cell proliferation and primary tumor growth. Conversely, CELSR2low cells display features of a more migratory phenotype. Collectively, our findings identify CELSR2 as a previously unknown regulator of epithelial-mesenchymal plasticity and reveal that heterogeneous CELSR2 expression shapes spatially and functionally distinct tumor cell populations, thereby contributing to intratumoral heterogeneity in TNBC.

cancer biology↗

bioRxiv2026

Circulating colorectal tumor cells remodel their surfaceome to increase their viability and metastatic potential in the bloodstream

Circulating tumor cells (CTCs) are the potential seeds of distant metastases; however, little is known about how they survive in the bloodstream. Using a large cohort of colorectal cancer (CRC) patients, we found that the pseudokinase receptor PTK7 is highly expressed in primary tumors and metastatic lesions. Consistent with previous reports, high PTK7 expression is associated with reduced disease-free survival and increased metastatic dissemination. Surprisingly, PTK7 is absent from most CTCs and undergoes a cell-autonomous ONtumor/OFFCTC/ONmetastasis switch that can be recapitulated in a xenografted mouse model, in in vitro systems, and a fluidic platform. PTK7-negative cancer cells exhibit increased expression of YAP1-driven genes, senescence-like features, and enhanced resistance to hemodynamic stress following loss of cell-cell and cell-matrix adhesion. This adaptive phenotype depends on metalloproteases, notably ADAM17, whose cleavage activity remodels the CTCs surfaceome. Functionally, the PTK7 OFFCTC state confers enhanced metastatic potential in vivo, and can be pharmacologically suppressed using metalloprotease inhibitors. Collectively, our findings identify a reversible, cell-autonomous, protease-driven surfaceome remodeling program that enables metastatic adaptation during hematogenous dissemination. Highlights / statement of significanceBy investigating potential markers for circulating colorectal tumor cells with strong metastatic potential, we describe a reversible and cell-autonomous remodeling of the circulating tumor cell surfaceome in patients that confers resistance to anoikis and stress induced by entry into the bloodstream. One Sentence SummaryThe dynamic regulation of PTK7 serves as a surrogate marker for tumor cell plasticity, aggressiveness, survival in the bloodstream, and efficiency in forming metastases. Trial registrationCTC colon Cohort: registered on https://ClinicalTrials.gov identifier NCT03256084; date of registration 2017-07-17 B-Org cohort: registered on https://ClinicalTrials.gov NCT05384184; date of registration 2019-06-06 Ethics statement for animal experimentsStudies on animals were conducted in accordance with the current ethical standards of the European Community (Directive 2010/63/EU), the Ethics Committee for Animal Experimentation (CEEA#14) and the French Ministry of Higher Education and Research, which approved and authorized the entire procedure described in this paper (project number APAFIS #35294).

cancer biology↗

bioRxiv2026

Multiomic dissection of HR+/HER2- invasive lobular breast carcinoma reveals mobilized yet dysfunctional anti-tumor immunity shaped by tumor-stroma crosstalk and impaired antigen presentation

ContextImmunotherapy based on immune checkpoint inhibitors (ICI) revolutionized the treatment of triple-negative (TN) breast carcinomas (BC), but remains more challenging in HR+/HER2- BCs. Because invasive lobular carcinomas (ILC) generally exhibit low immune infiltration, ICIs were largely overlooked in this pathological type. The only clinical trial of ICIs dedicated to ILCs showed disappointing results, notably in HR+/HER2- cases. The immune landscape of HR+/HER2- ILCs has been poorly described. High level of tumor-infiltrating lymphocytes (TIL) was associated with worse prognosis in HR+/HER2- ILCs. A better characterization of the immune landscape of HR+/HER2- ILCs could clarify the poor efficiency of ICIs and the negative prognostic value of TILs, and reveal complementary targets able to increase immunotherapy efficiency. MethodWe comprehensively characterized the immune landscape of HR+/HER2- ILCs, comparatively to HR+/HER2- invasive ductal carcinomas (IDC), by applying multi-omics and multi-scale analysis (gene expression at the bulk and single-cell levels, and protein-based spatial analysis) to clinical samples. ResultsWhile the overall level of immune infiltration was comparable between both pathological types, the quality of immune infiltrate differed markedly. Comparatively to HR+/HER2- IDCs, HR+/HER2- ILCs were enriched in immune cells and tertiary lymphoid structures with anti-tumor potential, presented more spatial proximity between cancer cells and CD8+ cytotoxic T cells, and stronger theorical vulnerability to ICIs. However, in HR+/HER2- ILCs, anti-tumor response was defective; CD8+ cytotoxic T cells failed to fully unleash their cytotoxic function and CD4+ helper T cells evidenced a pro-tumoral and naive phenotype. Furthermore, antigen-presenting compartment was defective, altogether embedded in a stronger immunosuppressive environment, enriched in immunoregulatory cancer-associated fibroblasts (iCAF). ConclusionThis study contributes to explain the lesser efficiency of PD-1/PD-L1-based ICIs in HR+/HER2-ILCs by comparison with HR+/HER2- IDCs, by shedding light on a complex ecosystem where tumor cells shape a distinctive stroma that contribute to prevent anti-tumor immune response activation. Altogether, our findings further support the rationale for combining iCAF-targeting strategy with an ad hoc immunotherapy (such as an anti-VTCN1/B7-H4 antibody-drug conjugates for example). Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/728418v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1dfbc7eorg.highwire.dtl.DTLVardef@1d030a7org.highwire.dtl.DTLVardef@12a3e84org.highwire.dtl.DTLVardef@6e6139_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_ST_ABSWHAT IS ALREADY KNOWN ON THIS TOPICC_ST_ABSO_LIImmune cells infiltrate both HR+/HER2- IDC and HR+/HER2- ILC tumors, but current ICIs are less effective in HR+/HER2- ILCs than HR+/HER2- IDCs. C_LI WHAT THIS STUDY ADDSO_LIThe anti-tumor immune response is mobilized but not effective in HR+/HER2- ILCs. C_LIO_LIA complex ecosystem - composed of immunoregulatory cancer-associated fibroblasts, high levels of TGFa, prostaglandin, acidosis, and a lack of antigen-presenting cells - prevents anti-tumor CD8+ cytotoxic T cell activation in HR+/HER2- ILCs. C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICYO_LITargeting the PD-1/PD-L1 axis is not the appropriate therapeutic strategy for HR+/HER2- ILCs. A more complex approach should be considered, notably those combining other immune-based strategies and iCAF targeting, which may offer a better chance to eradicate HR+/HER2- ILC tumor cells. C_LI

cancer biology↗

bioRxiv2026

TERT drives liver tumorigenesis beyond telomere elongation

We generated two mouse models, p21/Tert and p21/TertCi, expressing either telomerase reverse transcriptase (TERT) or a catalytically inactive variant under the control of the p21 promoter. By 18-20 months of age, approximately 25% of mice from both genotypes developed liver tumors with histopathological features resembling human hepatocellular carcinoma (HCC). Whole-exome sequencing identified activating Ctnnb1 mutations and recurrent PP1 subunit alterations in p21/Tert tumors, whereas p21/TertCi tumors harbored activating HrasGln61Lys mutations associated with elevated C>A transversions. Both models exhibited chromosomal aberrations commonly observed in human HCC. Transcriptomic analyses revealed that {beta}-catenin-activated tumors recapitulated gene expression signatures of human HCC, while MAPK-mutated tumors showed profiles consistent with MAPK/ERK pathway activation. Metabolically, both genotypes demonstrated increased glycolysis and suppression of gluconeogenesis, including downregulation of FBP1, but expressed distinct NRF2 target genes. Spatial profiling further revealed reduced HNF4-positive hepatocytes across tumors, independent of Hnf4 transcription, and markedly diminished immune cell infiltration particularly in {beta}-catenin-activated tumors. Collectively, these findings uncover telomere-independent functions of TERT and identify molecular and metabolic features with potential relevance for predicting immunotherapy response.

cancer biology↗

bioRxiv2025

TTLL6-mediated Polyglutamylation of PurA Maintains Colonic Crypt Integrity

The tubulin tyrosine ligase-like (TTLL) family comprises enzymes catalyzing posttranslational modifications of tubulin, including glutamylation and glycylation. We previously described a critical role for the monoglycylase TTLL3 in colon. Here, we identified TTLL6 as the predominant polyglutamylase in the colon, specifically expressed in epithelial cells of distal and transverse segments. TTLL6 expression decreases during CRC progression, correlating with poor patient prognosis. Deletion of Ttll6 in mice resulted in elongated colonic crypts, expansion of stem and transit-amplifying compartments, and increased numbers of differentiated epithelial cells. Moreover, Ttll6-deficient mice showed an elevated susceptibility to chemically induced colon carcinogenesis. Notably, we identified the nucleic acid-binding protein PurA as a novel TTLL6 substrate with both proteins mutually required for nuclear localization. Consistently, both nuclear polyglutamylation and PurA were present in the bottom compartment of control colons, but reduced in Ttll6-deficient colons. These findings reveal a TTLL6-PurA axis being critical in maintaining colonic homeostasis.

cell biology↗

bioRxiv2025

Multi-omic analysis of colorectal adenocarcinoma identifies a new subtype of myofibroblastic cancer-associated fibroblast expressing high level of B7-H3 and with poor prognosis value.

The high mortality rate of colorectal cancer (CRC) combined with the lack of non-toxic and efficient personalized treatments makes it urgent to develop new targeted therapies for this disease. B7-H3 appears to be a good target as it is overexpressed in tumor tissue compared to normal tissue. However, B7-H3 is a molecule with ambivalent functions and is expressed by different cell types. This complexity contributed to the delay in identifying cell subtypes that express B7-H3 and their potential role in colorectal oncogenesis. In this study, we used in silico bulk, single-cell, and spatial transcriptomic data to investigate the clinical and biological characteristics of tumors with high B7-H3 expression, the precise nature of cells expressing high level of B7-H3, and their temporal appearance during colorectal oncogenesis. We found that tumors with high B7-H3 expression corresponded to tumors with a predominant stroma composed mainly of fibroblasts. Among them, two subtypes of ecm-myCAF fibroblasts and pro-fibrotic pericytes specifically expressed high levels of B7-H3, the former being an independent factor for poor prognosis in CRC. Finally, by examining precancerous lesions, we report that fibroblast subtypes with high levels of B7-H3 appear early during oncogenesis, especially at the inflamed stage. We also shed light on the fact that anti-B7-H3 immunotherapies might therefore preferentially target cells from the microenvironment rather than the tumor cells. This is particularly important to understand the mode of action of the anti-B7-H3 antibody-drug conjugate, which is currently being tested in clinical trials in several solid tumors. HighlightsO_LIHigh level of B7-H3 expression is associated with poor prognosis in colorectal cancer C_LIO_LIB7-H3 is recurrently found expressed by two subtypes of cancer-associated fibroblasts (CAF): pro-fibrotic pericytes and ecm-myCAF C_LIO_LIB7-H3high ecm-myCAF subtype is an independent poor prognosis for survival C_LIO_LIB7-H3high ecm-myCAF is detectable in pre-cancerous inflamed colonic tissues C_LI

cancer biology↗

bioRxiv2025

Multiscale Modeling Uncovers Macrophage Infiltration and TNF-α Signaling Networks for Targeting in Inflammatory Breast Cancer Tumor Emboli

Inflammatory breast cancer (IBC) tumors are characterized by diffuse clusters of cells found in dermal tissue and lymphatic vessels, known as tumor emboli. Thus, IBC needs a novel treatment because it is the most aggressive breast cancer subtype. We hypothesized that the interaction between tumor emboli and the tumor immune microenvironment (TiME) fosters survival signaling, leading to the aggressiveness of the IBC. In this study, ex vivo tumor emboli were generated from patient-derived cell lines cultured in a lymphatic-like environment, which was compared to 2D monolayer cultures, revealing upregulation of TNFR signaling networks, CXCL8, and immune cell chemotaxis genes. Spatial immunophenotyping of IBC patient tumors demonstrated high levels of CD163+ tumor-associated macrophages (TAMs). Furthermore, intravital imaging of CX3cr1GFP mice confirmed macrophage movement toward tumor cell clusters. Finally, targeting macrophage-associated TNF--signaling using Birinapant, a SMAC mimetic, inhibited the tumor emboli phenotype in vivo, identifying Birinapant as a potential therapeutic agent to disrupt this signaling axis.

cancer biology↗

bioRxiv2025

The extracellular matrix drives guanylate production and protects pancreatic cancer cells from oxaliplatin-induced DNA damage.

The excessive production of extracellular matrix (ECM) and the metabolic adaptations in pancreatic ductal adenocarcinoma (PDAC) contribute individually to enhanced chemoresistance, dramatic tumor progression and dismal patient survival. However, ECM-driven metabolic alterations that promote chemoresistance in PDAC are so far unexplored. Here, we use in-vitro-generated ECM bio-scaffolds that recapitulate cell-ECM interactions and induce broad metabolic alterations in PDAC cells. High-throughput integration of multi-omics datasets coupled with metabolic tracing showed that the ECM enhances the generation of guanylates in PDAC cells, the accumulation of which alleviates oxaliplatin-induced DNA damage, and boosts PDAC cell proliferation. These events are guided by the guanosine monophosphate (GMP)-producing enzymes Impdh and Gmps, the expression of which correlated with that of matrisomal and DNA repair genes in PDAC patient samples. We propose that targeting ECM-driven metabolic processes, like the enhanced Impdh activity, may be an effective therapeutic approach for PDAC patients that bypasses the negative side effects of direct targeting of the ECM itself.

cancer biology↗

bioRxiv2024

Visualization and quantification of coral reef soundscapes using CoralSoundExplorer software

Despite hosting some of the highest concentrations of biodiversity and providing invaluable goods and services in the oceans, coral reefs are under threat from global change and other local human impacts. Changes in living ecosystems often induce changes in their acoustic characteristics, but despite recent efforts in passive acoustic monitoring of coral reefs, rapid measurement and identification of changes in their soundscapes remains a challenge. Here we present the new open-source software CoralSoundExplorer (https://sound-scape-explorer.github.io/docs/CSE/), which is designed to study and monitor coral reef soundscapes. CoralSoundExplorer uses deep learning approaches and is designed to eliminate the need to extract conventional acoustic indices. To demonstrate CoralSoundExplorers functionalities, we use and analyze a set of recordings from three coral reef sites, each with different purposes (undisturbed site, tourist site and boat site) located on the island of Bora-Bora in French Polynesia. We explain the CoralSoundExplorer analysis workflow, from raw sounds to ecological results, detailing and justifying each processing step. We detail the software settings, the graphical representations used for visual exploration of soundscapes and their temporal dynamics, along with the analysis methods and metrics proposed. We demonstrate that CoralSoundExplorer is a powerful tool for identifying disturbances affecting coral reef soundscapes, combining visualizations of the spatio-temporal distribution of sound recordings with new quantification methods to characterize soundscapes at different temporal scales. Author summaryTodays scientists are faced with the challenge of analyzing large amounts of data, such as those generated by passive acoustic monitoring of ecosystems. We have built CoralSoundExplorer (https://sound-scape-explorer.github.io/docs/CSE/), an efficient tool for analyzing large datasets of sound recordings, which transforms coral reef soundscape recordings into visual representations in 2D or 3D spaces. By spreading them across easy-to-explore acoustic spaces, CoralSoundExplorer enables the observer to quickly grasp the characteristics of soundscapes, their differences and similarities, and their organization on different temporal scales. These acoustic spaces and their temporal dynamics can be quantified, for example to account for the speed at which soundscapes change over time. In this study, we take the example of reef soundscapes from the island of Bora-Bora to illustrate the features and possibilities offered by CoralSoundExplorer. CoralSoundExplorer is open source and easy to use, even for non-specialists, thanks to an interface that requires no coding skills. We provide detailed instructions for installing and using CoralSoundExplorer to help users get started easily. CoralSoundExplorer needs to be installed on a computer to perform the analyses and calculations based on sound recordings. There is also an online interface (https://sound-scape-explorer.github.io/coral-sound-explorer/) enabling users to visualize data that have already been processed by CoralSoundExplorer.

ecology↗

bioRxiv2022

Validation of a novel fully immersive Virtual Reality setup with a behavioural study of freely-moving fish

Virtual Reality (VR) enables standardised stimuli to invoke behavioural responses in animals, however, in fish studies VR has been limited to either basic virtual stimulation projected below the bowl for freely-swimming individuals or a simple virtual arena rendered over a large field-of-view for head-restrained individuals. We developed a novel immersive VR setup with real-time rendering of animated 3D scenarios, validated in a proof of concept study on the behaviour of coral reef post-larval fish. Fish use a variety of cues to select a habitat during the recruitment stage, and to recognize conspecifics and predators, but which visual cues are used remains unknown. We measured behavioural responses of groups of five convict surgeonfish (Acanthurus triostegus) to simulations of habitats, static or moving shoals of conspecifics, predators, and non-aggressive heterospecifics. Post-larval fish were consistently attracted to virtual corals and conspecifics presented statically, but repulsed by their predators (bluefin jacks, Caranx melampygus). When simulated shoals passed nearby repeatedly, they were again attracted by conspecifics showing a tendency to follow the shoal, whereas they moved repeatedly to the back of the passing predator shoal. They also discriminated between species of similar sizes: they were attracted more to conspecifics than butterflyfish (Forcipiger longirostris), and repulsed more by predators than parrotfish (Scarus psittacus). The quality of visual simulations was high enough to identify between visual cues - size, body shape, colour pattern - used by post-larval fish in species recognition. Despite a tracking technology limited to fish 2D positions in the aquarium, preventing the real-time updating of the rendered viewpoint, we could show that VR and modern tracking technologies offer new possibilities to investigate fish behaviour through the quantitative analysis of their physical reactions to highly-controlled scenarios.

animal behavior and cognition↗

bioRxiv2021

The serine/threonine kinase MINK1 directly regulates the function of promigratory proteins

Upregulation of the developmental Wnt/planar cell polarity pathway is observed in many cancers and is associated with cancer development at early and late stages. We recently showed that PRICKLE1 and VANGL2, two core Wnt/PCP components, are overexpressed in triple negative breast cancer and associated with poor prognosis. PRICKLE1 is a cytoplasmic protein phosphorylated by the poorly described serine/threonine kinase MINK1 which triggers its localization at the plasma membrane, a key step for its function. Knockdown experiments have demonstrated that MINK1 and PRICKLE1 contribute to TNBC cell motility and spreading in vitro and in vivo. However, the identity of MINK1 substrates and the role of MINK1 enzymatic activity in this process have not yet been addressed issues. We carried out a phosphoproteomic strategy and identified novel MINK1 substrates including LL5{beta}. LL5{beta} is a membrane scaffold molecule that anchors microtubules at the cell cortex through its association with the plus-end MT proteins CLASPs to trigger focal adhesion disassembly. LL5{beta} is a prominent member of the MINK1-PRICKLE1 protein complex and is directly phosphorylated by MINK1 that promotes its interaction with CLASP. Using a kinase inhibitor, we demonstrate that the enzymatic activity of MINK1 is involved in the protein complex assembly and localization, and cell migration. Analysis of gene expression data show that the concomitant up-regulation of PRICKLE1 and LL5{beta} mRNA levels encoding MINK1 substrates is associated with a poor metastasis-free survival for TNBC patients. Altogether, our results suggest that MINK1 may represent a potential target in TNBC.

cell biology↗

bioRxiv2021

Lipocalin 2 promotes inflammatory breast cancer tumorigenesis and skin invasion

Inflammatory breast cancer (IBC) is an aggressive form of primary breast cancer characterized by rapid onset and high risk of metastasis and poor clinical outcomes. The biological basis for the aggressiveness of IBC is still not well understood and no IBC-specific targeted therapies exist. In this study we report that lipocalin 2 (LCN2), a small secreted glycoprotein belonging to the lipocalin superfamily, is expressed at significantly higher levels in IBC versus non-IBC tumors, independently of molecular subtype. LCN2 levels were also significantly higher in IBC cell lines and in their culture media than in non-IBC cell lines. High expression was associated with poor-prognosis features and shorter overall survival in IBC patients. Depletion of LCN2 in IBC cell lines reduced proliferation, colony formation, migration, and cancer stem cell populations in vitro, and inhibited tumor growth, skin invasion, and brain metastasis in mouse models of IBC. Analysis of our proteomics data showed reduced expression of proteins involved in cell cycle and DNA repair in LCN2-silenced IBC cells. Our findings support that LCN2 promotes IBC tumor aggressiveness and offer a new potential therapeutic target for IBC.

cancer biology↗

bioRxiv2020

EFA6B regulates a stop signal for collective invasion in breast cancer

Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes, however additional mutations provide selective advantages to the tumor cells to resist treatment and develop metastases, therefore identification of secondary mutations is of paramount importance. EFA6B (Exchange Factor for ARF6, B) expression is reduced in breast cancer. To study the pro-tumoral impact of the loss of EFA6B we have invalidated its gene in normal human mammary cells. We found that EFA6B knock-out triggers a transcriptional reprogramming of the cell-to-ECM interaction machinery and unleashes CDC42-dependent collective invasion in collagen. In addition, invasive and metastatic tumors isolated from patients have lower expression of EFA6B and display gene ontology signatures identical to those of EFA6B knock-out cells. Thus, we reveal a new EFA6B-regulated molecular mechanism that controls the invasive potential of mammary cells; this finding opens up new avenues for the treatment of invasive breast cancer.

cancer biology↗

bioRxiv2019

Loss of cyclin A2 in murine colonic epithelial cells disrupts colon homeostasis by triggering DNA damage and dysplasia and high cyclin A2 expression is a good-prognosis factor in patients with colorectal cancer

To clarify the function of cyclin A2 in colon homeostasis and colorectal cancer (CRC) we generated mice deficient for cyclin A2 in colonic epithelial cells (CEC). Colons of those mice displayed architectural changes in the mucosa, and signs of inflammation as well as an increased proliferation of CEC associated with the appearance of low- and high-grade dysplasia. The main initial events triggering those alterations in cyclin A2 deficient CEC appear to be abnormal mitoses and DNA damage. Cyclin A2 deletion in CEC promoted the development of dysplasia and adenocarcinomas in the murine colitis-associated cancer model. We next explored the status of cyclin A2 expression in clinical CRC samples at the mRNA and protein level and found higher expression in tumors of stage I and II patients compared to those of stage III and IV. A meta-analysis of 11 transcriptome datasets comprising 2,239 primary CRC tumors displayed different CCNA2 (the mRNA coding for cyclin A2) expression levels among the CRC tumor subtypes with highest in CMS1 and lowest in CMS4. Moreover, high expression of CCNA2 was found to be a good prognosis factor independently from other prognostic factors for the CMS1, CMS3 and CMS4 subtypes.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC=\"FIGDIR/small/690404v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (36K):\norg.highwire.dtl.DTLVardef@d9de04org.highwire.dtl.DTLVardef@17f0b4forg.highwire.dtl.DTLVardef@1bf9748org.highwire.dtl.DTLVardef@16520df_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Conditional activation of immune-related signatures and prognostic significance: a pan-cancer analysis

BackgroundIt is becoming clear that tumor immune T cell infiltration and its functional orientation have substantial effect on cancer progression, influencing both response to therapy and prognosis. In this pan-cancer study, the previously described Immunologic Constant of Rejection (ICR) signature is used to define opposing immune phenotypes (i.e., immuneactive and immune-silent) across 31 different histologies. We systematically analyze the interconnections between the genetic programming of neoplasms and their immune orientation across different histologies, and the prognostic impact of such interplay. Moreover, we investigated the predictive value of ICR classification across various public datasets of immune checkpoint inhibition therapy. MethodsRNA-seq data of samples from a total of 9,282 patient tumor samples representing 31 cancer types were obtained from The Cancer Genome Atlas (TCGA). We classified each cancer type based on the expression of the ICR gene signature. Oncogenic pathway gene set enrichment and mutational status were analyzed in relation to ICR phenotypes. To explore whether tumorintrinsic attributes associate with the prognostic value of ICR across cancers, we compared mutational load, oncogenic alterations and expression of oncogenic pathways between cancer types using an integrative bioinformatic pipeline. ResultsOur analyses identified a distinct prognostic connotation of ICR depending on cancer histology. We identified several oncogenic pathways whose enrichment inversely correlated with ICR in multiple tumor types. We found several cancer specific pathways that were differentially enriched between tumors in which ICR had a prognostic impact versus the ones in which ICR did not bear any prognostic connotation such as proliferation and TGF-beta signaling. Importantly, this conditional impact of ICR was also validated in the context of immune checkpoint inhibition treatment. ConclusionsWe identified tumor-intrinsic attributes that correlate with immune phenotypes and potentially influence their development. In addition, a relationship was observed between the enrichment of oncogenic pathways and the prognostic significance of the ICR and its predictive value for patients treated with anti-CTLA4 immune checkpoint inhibition. Such information can be used to prioritize potential candidates for therapies aimed at converting immune-silent into immuneactive tumors and to refine stratification algorithms.

cancer biology↗

bioRxiv2018

ECT2 associated to PRICKLE1 are poor-prognosis markers in triple-negative breast cancer

BackgroundTriple-negative breast cancers are poor-prognosis tumors characterized by absence of molecular signature and are chemotherapy is still the only systemic treatment. Currently, research focus to identify biomarkers that may be usable for prognosis and/or for treatment, notably among the proteins involved in cell migration and metastatic capacity.\n\nMethodsWe used proteomic approach to identify protein complexes associated to PRICKLE1 and the mRNA expression level of the corresponding genes in a retrospective series of 8,982 clinically annotated patients with invasive primary breast cancer were assessed. Then, we characterize molecularly the interaction between PRICKLE1 and the guanine nucleotide exchange factor ECT2. Finally, experiments in Xenopus have been carrying out to determine their evolutionary conserved interaction.\n\nResultsWe have identified a network of proteins interacting with the prometastatic scaffold protein PRICKLE1 that includes several small G-protein regulators involved in cell migration and metastasis. Combined analysis expression of PRICKLE1 and small G-protein regulators expression has a strong prognostic value in TNBC. We show that PRICKLE1 controls the activity of ECT2 on RAC1 signaling, a pathway required for cancer cell dissemination.\n\nConclusionsThis work supports the idea that promigratory proteins, which are overexpressed in cancerous epithelium, are suitable pharmaceutical targets.

cancer biology↗