Journal: Cancer Research

Abbreviation

Cancer Res

Publisher

American Association for Cancer Research

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ISSN

0008-5472
1538-7445

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Publications 1 - 10 of 56
  • JMJD6 Is a druggable oxygenase that regulates AR-V7 expression in prostate cancer
    Item type: Journal Article
    Paschalis, Alec; Welti, Jonathan; Neeb, Antje J.; et al. (2021)
    Cancer Research
    Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P < 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease. © 2021 American Association for Cancer Research
  • A Protumorigenic mDia2-MIRO1 Axis Controls Mitochondria! Positioning and Function in Cancer-Associated Fibroblasts
    Item type: Journal Article
    Cangkrama, Michael; Liu, Huan; Whipman, James; et al. (2022)
    Cancer Research
    Cancer-associated fibroblasts (CAF) are key regulators of tumorigenesis. Further insights into the tumor-promoting mechanisms of action of CAFs could help improve cancer diagnosis and treatment. Here we show that the formin mDia2 regulates the positioning and function of mitochondria in dermal fibroblasts, thereby promoting a protumorigenic CAF phenotype. Mechanistically, mDia2 stabilized the mitochondrial trafficking protein MIRO1. Loss of mDia2 or MIRO1 in fibroblasts or CAFs reduced the presence of mitochondria and ATP levels near the plasma membrane and at CAF-tumor cell contact sites, caused metabolic alterations characteristic of mitochondrial dysfunction, and suppressed the secretion of protumorigenic proteins. In mouse models of squamous carcinogenesis, genetic or pharmacologic inhibition of mDia2, MIRO1, or their common upstream regulator activin A inhibited tumor formation. Consistently, co-upregulation of mDia2 and MIRO1 in the stroma of various human cancers negatively correlated with survival. This work unveils a key role of mitochondria in the protumorigenic CAF phenotype and identifies an activin A-mDia2-MIRO1 signaling axis in CAFs with diagnostic and therapeutic potential.
  • Tumor Suppressor VHL Functions in the Control of Mitotic Fidelity
    Item type: Journal Article
    Hell, Michael P.; Duda, Maria; Weber, Thomas C.; et al. (2014)
    Cancer Research
  • Novel matrix metalloproteinase inhibitor [18F]marimastat-aryltrifluoroborate as a probe for in vivo positron emission tomography imaging in cancer
    Item type: Journal Article
    auf dem Keller, Ulrich; Bellac, Caroline L.; Li, Ying; et al. (2010)
    Cancer Research
  • miR-28-5p Promotes Chromosomal Instability in VHL-Associated Cancers by Inhibiting Mad2 Translation
    Item type: Journal Article
    Hell, Michael P.; Thoma, Claudio R.; Fankhauser, Niklaus; et al. (2014)
    Cancer Research
  • Abstract 389: Integrating diverse transcriptomic alterations to identify cancer-relevant genes
    Item type: Other Conference Item
    Davidson, Natalie R.; PanCancer Analysis of Whole Genomes 3 (PCAWG-3) for ICGC; Brazma, Alvis; et al. (2017)
    Cancer Research ~ Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC
  • Volumetric optoacoustic imaging unveils high-resolution patterns of acute and cyclic hypoxia in a murine model of breast cancer
    Item type: Journal Article
    Ron, Avihai; Dean-Ben, Xose Luis; Gottschalk, Sven; et al. (2019)
    Cancer Research
  • Coupling of mutated met variants to DNA repair via Abl and Rad51
    Item type: Journal Article
    Ganapathipillai, Suganthini S.; Medova, Michaela; Aebersold, Daniel M.; et al. (2008)
    Cancer Research
  • Metastasis Unleashed: Hyposialylation Empowers Chemo-Evasive Circulating Tumor Cell Clusters in Breast Cancer
    Item type: Journal Article
    Gvozdenovic, Ana; Aceto, Nicola (2023)
    Cancer Research
    Therapy resistance is frequently observed in cancer patients with distant metastases and effective management of metastatic disease remains challenging. Unraveling the cellular mechanisms and molecular targets fueling metastatic spread is crucial for advancing cancer therapies. In a recent issue of Cancer Discovery, Dashzeveg and colleagues revealed that loss of terminal sialylation in glycoproteins within circulating tumor cell clusters is a dynamic process that contributes to cellular dormancy, facilitates evasion of chemotherapy, and enhances metastatic seeding. Furthermore, the study identifies the glycoprotein podocalyxin (PODXL) as a potential target for counteracting the metastasis of quiescent tumor cells associated with paclitaxel treatment in triple-negative breast cancer.
  • Functional analysis identifies damaging CHEK2 missense variants associated with increased cancer risk
    Item type: Journal Article
    Boonen, Rick; Wiegant, Wouter W; Celosse, Nandi; et al. (2022)
    Cancer Research
    Heterozygous carriers of germline loss-of-function variants in the tumor suppressor gene checkpoint kinase 2 (CHEK2) are at an increased risk for developing breast and other cancers. While truncating variants in CHEK2 are known to be pathogenic, the interpretation of missense variants of uncertain significance (VUS) is challenging. Consequently, many VUS remain unclassified both functionally and clinically. Here we describe a mouse embryonic stem (mES) cell-based system to quantitatively determine the functional impact of 50 missense VUS in human CHEK2. By assessing the activity of human CHK2 to phosphorylate one of its main targets, Kap1, in Chek2 knockout mES cells, 31 missense VUS in CHEK2 impaired protein function to a similar extent as truncating variants, and 9 CHEK2 missense VUS resulted in intermediate functional defects. Mechanistically, most VUS impaired CHK2 kinase function by causing protein instability or by impairing activation through (auto)phosphorylation. Quantitative results showed that the degree of CHK2 kinase dysfunction correlates with an increased risk for breast cancer. Both damaging CHEK2 variants as a group (OR 2,23; 95% CI 1,62-3,07; p<0,0001) and intermediate variants (OR 1,63; 95% CI 1,21-2,20; p=0,0014) were associated with an increased breast cancer risk, while functional variants did not show this association (OR 1,13; 95% CI 0,87-1,46; p=0,378). Finally, a damaging VUS in CHEK2, c.486A>G/p.D162G, was also identified, which co-segregated with familial prostate cancer. Altogether, these functional assays efficiently and reliably identified VUS in CHEK2 that associate with cancer.
Publications 1 - 10 of 56