Biology subjects

Moiso, E.

Publications and source records attributed to Moiso, E..

5 recordsLinked to original sources

bioRxiv2024

Mutant p53 Exploits Enhancers to Elevate Immunosuppressive Chemokine Expression and Impair Immune Checkpoint Inhibitors in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations dysregulate cancer-cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we show that p53R172H establishes an immunosuppressive TME, diminishes the efficacy of immune checkpoint inhibitors (ICIs), and enhances tumor growth. Our findings reveal that the upregulation of the immunosuppressive chemokine Cxcl1 mediates these pro-tumorigenic functions of p53R172H. Mechanistically, we show that p53R172H associates with the distal enhancers of the Cxcl1 gene, increasing enhancer activity and Cxcl1 expression. p53R172H occupies these enhancers in an NF-{kappa}B-pathway-dependent manner, suggesting NF-{kappa}Bs role in recruiting p53R172H to the Cxcl1 enhancers. Our work uncovers how a common mutation in a tumor-suppressor transcription factor appropriates enhancers, stimulating chemokine expression and establishing an immunosuppressive TME that diminishes ICI efficacy in PDAC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/609802v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@b2354dorg.highwire.dtl.DTLVardef@1c96300org.highwire.dtl.DTLVardef@829f26org.highwire.dtl.DTLVardef@19e7d2e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Homologous recombination deficiency and tumor suppressor heterozygosity mediate resistance to front-line therapy in breast cancer

The co-occurrence of germline and somatic oncogenic alterations is frequently observed in breast cancer, but their combined biologic and clinical significance has not been evaluated. To assess the role of germline-somatic interactions on outcomes in routine practice, we developed an integrated clinicogenomic pipeline to analyze the genomes of over 4,500 patients with breast cancer. We find that germline (g)BRCA2-associated tumors are enriched for RB1 loss-of-function mutations and manifest poor outcomes on standard-of-care, front-line CDK4/6 inhibitor (CDK4/6i) combinations. Amongst these tumors, gBRCA2-related homologous recombination deficiency (HRD) as well as baseline RB1 LOH status promote acquisition of RB1 loss-of- function mutations under the selective pressure of CDK4/6i, causing therapy resistance. These findings suggest an alternative therapeutic strategy using sequential targeting of HRD in gBRCA- associated breast cancers through PARP inhibitors prior to CDK4/6i therapy to intercept deleterious RB1-loss trajectories and thus suppress the emergence of CDK4/6 inhibitor resistance. More broadly, our findings demonstrate how germline-somatic driven genomic configurations shape response to systemic therapy and can be exploited therapeutically as part of biomarker-directed clinical strategies.

genomics↗

bioRxiv2021

Cancer metabolic subtypes and their association with molecular and clinical features

Alterations of metabolic pathways in cancer have been investigated for many years, beginning way before the discovery of the role of oncogenes and tumor suppressors, and the last few years have witnessed a renewed interest in this topic. Large-scale molecular and clinical data on tens of thousands of samples allow us today to tackle the problem from a general point of view. Here we show that transcriptomic profiles of tumors can be exploited to define metabolic cancer subtypes, which can be systematically investigated for association with other molecular and clinical data. We find thousands of significant associations between metabolic subtypes and molecular features such as somatic mutations, structural variants, epigenetic modifications, protein abundance and activation; and with clinical/phenotypic data including survival probability, tumor grade, and histological types. Our work provides a methodological framework and a rich database of statistical associations, accessible from metaminer.unito.it, that will contribute to the understanding of the role of metabolic alterations in cancer and to the development of precision therapeutic strategies.

cancer biology↗

bioRxiv2021

Hematopoiesis at single cell resolution spanning human development and maturation

Hematopoiesis is a process of constitutive regeneration whereby hematopoietic stem and progenitor cells (HSPCs) replenish mature blood cells. During maturation and aging, HSPCs shift their output to support the demands of prenatal development and postnatal maturation both at homeostasis and in response to stress. How HSPC ontogeny changes throughout life is unknown; studies to date have largely focused on specific individual ages, particularly at single cell resolution. Here, we performed single cell RNA-seq of human HSPCs from early prenatal development into mature adulthood. We observed shifts in HSPC transcriptional states and differentiation trajectories over time. We identified age-specific gene expression patterns throughout human maturation and developed methods for identifying, prospectively purifying, and functionally validating age-specific HSC states. Together, our findings define the temporal maturation of human HSPCs and uncover principles applicable to age-biased blood diseases. SummarySingle cell RNA sequencing reveals that the mechanisms of human hematopoietic stem and progenitor cell (HSPC) fate commitment change over a lifetime from gestation to mature adulthood.

developmental biology↗

bioRxiv2018

SP1 and STAT3 functionally synergize to induce the RhoU small GTPase and a subclass of non-canonical WNT responsive genes correlating with poor prognosis in breast cancer.

Breast cancer is a complex disease in which heterogeneity makes clinical management very challenging. Although breast cancer subtypes classified according to specific molecular features are associated to better or worse prognosis, the identification of specific markers predicting disease outcome within the single subtypes still lags behind. Both the non-canonical WNT and the STAT3 pathways are often constitutively activated in breast tumors, and both can induce the small GTPase RhoU gene transcription. Here we show that RhoU transcription can be triggered by both canonical and non-canonical WNT ligands via the activation of JNK and the recruitment of the SP1 transcription factor to the RhoU promoter, identifying for the first time SP1 as a JNK-dependent mediator of WNT signaling. RhoU down-regulation by silencing or treatment with JNK, SP1 or STAT3 inhibitors lead to impaired cell migration in basal-like MDA-MB-231 cells, which display constitutive activation of both the non-canonical WNT and STAT3 pathways. These data suggest that STAT3 and SP1 can cooperate to induce high RhoU expression and enhance migration of breast cancer cells. In vivo binding of both factors characterizes a group of SP1/STAT3 responsive genes belonging to the non-canonical WNT and the IL-6/STAT3 pathways. High expression of this signature is significantly correlated with poor prognosis across all profiled patients. Thus, concomitant binding of both STAT3 and SP1 defines a subclass of genes contributing to breast cancer aggressiveness, suggesting the relevance of developing novel targeted therapies combining inhibitors of the STAT3 and WNT pathways or of their downstream mediators.\n\nNovelty and ImpactThe WNT and STAT3 pathways are often activated in breast tumors, but whether they can cooperate towards aggressiveness is not presently known. Here the authors show that WNT ligands can elicit the activation of the transcription factor SP1, which cooperates with STAT3 to induce a subset of non-canonical WNT and IL-6/STAT3 genes. Expression of this gene signature correlates with bad prognosis in breast cancer, suggesting coordinated interference with both TFs as a novel therapeutic option.

cancer biology↗