Journal: Molecular Oncology

Abbreviation

Mol Oncol

Publisher

Wiley

Journal Volumes

ISSN

1574-7891
1878-0261

Description

Filters

2015 - 201922020 - 20244
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Publications 1 - 6 of 6
  • Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics
    Item type: Journal Article
    Bensimon, Ariel; Koch, Jonas P.; Francica, Paola; et al. (2020)
    Molecular Oncology
    Increasing evidence suggests that interference with growth factor receptor tyrosine kinase (RTK) signaling can affect DNA damage response (DDR) networks, with a consequent impact on cellular responses to DNA‐damaging agents widely used in cancer treatment. In that respect, the MET RTK is deregulated in abundance and/or activity in a variety of human tumors. Using two proteomic techniques, we explored how disrupting MET signaling modulates global cellular phosphorylation response to ionizing radiation (IR). Following an immunoaffinity‐based phosphoproteomic discovery survey, we selected candidate phosphorylation sites for extensive characterization by targeted proteomics focusing on phosphorylation sites in both signaling networks. Several substrates of the DDR were confirmed to be modulated by sequential MET inhibition and IR, or MET inhibition alone. Upon combined treatment, for two substrates, NUMA1 S395 and CHEK1 S345, the gain and loss of phosphorylation, respectively, were recapitulated using invivo tumor models by immunohistochemistry, with possible utility in future translational research. Overall, we have corroborated phosphorylation sites at the intersection between MET and the DDR signaling networks, and suggest that these represent a class of proteins at the interface between oncogene‐driven proliferation and genomic stability.
  • High-throughput proteomic analysis of FFPE tissue samples facilitates tumor stratification
    Item type: Journal Article
    Zhu, Yi; Weiss, Tobias; Zhang, Qiushi; et al. (2019)
    Molecular Oncology
    Formalin‐fixed, paraffin‐embedded (FFPE), biobanked tissue samples offer an invaluable resource for clinical and biomarker research. Here, we developed a pressure cycling technology (PCT)‐SWATH mass spectrometry workflow to analyze FFPE tissue proteomes and applied it to the stratification of prostate cancer (PCa) and diffuse large B‐cell lymphoma (DLBCL) samples. We show that the proteome patterns of FFPE PCa tissue samples and their analogous fresh‐frozen (FF) counterparts have a high degree of similarity and we confirmed multiple proteins consistently regulated in PCa tissues in an independent sample cohort. We further demonstrate temporal stability of proteome patterns from FFPE samples that were stored between 1 and 15 years in a biobank and show a high degree of the proteome pattern similarity between two types of histological regions in small FFPE samples, that is, punched tissue biopsies and thin tissue sections of micrometer thickness, despite the existence of a certain degree of biological variations. Applying the method to two independent DLBCL cohorts, we identified myeloperoxidase, a peroxidase enzyme, as a novel prognostic marker. In summary, this study presents a robust proteomic method to analyze bulk and biopsy FFPE tissues and reports the first systematic comparison of proteome maps generated from FFPE and FF samples. Our data demonstrate the practicality and superiority of FFPE over FF samples for proteome in biomarker discovery. Promising biomarker candidates for PCa and DLBCL have been discovered.
  • Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment
    Item type: Journal Article
    Hariharan, Ananya; Qi, Weihong; Rehrauer, Hubert; et al. (2022)
    Molecular Oncology
    We previously observed increased levels of adenosine-deaminase-acting-on-dsRNA (Adar)-dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR-dependent RNA editing in mesothelioma. We found that tumors and mesothelioma primary cultures have higher ADAR-mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1-associated protein 1 wild-type tumors, with corresponding changes in RNA editing in transcripts and 3'UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment, and type-1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also in chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures.
  • Integrative analysis of cancer imaging readouts by networks
    Item type: Review Article
    Dominietto, Marco; Tsinorernas, Nicholas; Capobianco, Enrico (2015)
    Molecular Oncology
    Cancer is a multifactorial and heterogeneous disease. The corresponding complexity appears at multiple levels: from the molecular and the cellular constitution to the macroscopic phenotype, and at the diagnostic and therapeutic management stages. The overall complexity can be approximated to a certain extent, e.g. characterized by a set of quantitative phenotypic observables recorded in time-space resolved dimensions by using multimodal imaging approaches. The transition from measures to data can be made effective through various computational inference methods, including networks, which are inherently capable of mapping variables and data to node- and/or edge-valued topological properties, dynamic modularity configurations, and functional motifs. We illustrate how networks can integrate imaging data to explain cancer complexity, and assess potential pre-clinical and clinical impact.
  • Alone you go faster, together you go farther
    Item type: Other Journal Item
    Aceto, Nicola (2024)
    Molecular Oncology
    The metastatic process is an extraordinarily complex step-by-step procedure, characterized by many analogies with migratory patterns of humans or animals across our planet. The ongoing interrogation of circulating tumor cells (CTCs), caught in the act of spreading from one location to another, is revealing distinct behaviors including biological, physical, and mechanical features that impact on their likelihood to form metastasis. In this viewpoint, I will discuss some of these findings and provide a perspective on the metastatic journey, open questions and opportunities to exploit some of the most recent discoveries for the development of antimetastasis medicines.
  • Immune escape of colorectal tumours via local LRH-1/Cyp11b1-mediated synthesis of immunosuppressive glucocorticoids
    Item type: Journal Article
    Ahmed, Asma; Reinhold, Cindy; Breunig, Eileen; et al. (2023)
    Molecular Oncology
    Control of tumour development and growth by the immune system critically defines patient fate and survival. What regulates the escape of colorectal tumours from destruction by the immune system remains currently unclear. Here, we investigated the role of intestinal synthesis of glucocorticoids in the tumour development during an inflammation-induced mouse model of colorectal cancer. We demonstrate that the local synthesis of immunoregulatory glucocorticoids has dual roles in the regulation of intestinal inflammation and tumour development. In the inflammation phase, LRH-1/Nr5A2-regulated and Cyp11b1-mediated intestinal glucocorticoid synthesis prevents tumour development and growth. In established tumours, however, tumour-autonomous Cyp11b1-mediated glucocorticoid synthesis suppresses anti-tumour immune responses and promotes immune escape. Transplantation of glucocorticoid synthesis-proficient colorectal tumour organoids into immunocompetent recipient mice resulted in rapid tumour growth, whereas transplantation of Cyp11b1-deleted and glucocorticoid synthesis-deficient tumour organoids was characterized by reduced tumour growth and increased immune cell infiltration. In human colorectal tumours, high expression of steroidogenic enzymes correlated with the expression of other immune checkpoints and suppressive cytokines, and negatively correlated with overall patients' survival. Thus, LRH-1-regulated tumour-specific glucocorticoid synthesis contributes to tumour immune escape and represents a novel potential therapeutic target.
Publications 1 - 6 of 6