Tropomyosin1 isoforms underlie epithelial to mesenchymal plasticity, metastatic dissemination, and resistance to chemotherapy in high-grade serous ovarian cancer

被引:3
作者
Xu, Tong [1 ]
Verhagen, Mathijs P. [1 ]
Teeuwssen, Miriam [1 ,6 ]
Sun, Wenjie [2 ]
Joosten, Rosalie [1 ]
Sacchetti, Andrea [1 ]
Ewing-Graham, Patricia C. [1 ]
Jansen, Maurice P. H. M. [3 ]
Boere, Ingrid A. [3 ]
Bryce, Nicole S. [4 ,7 ]
Zeng, Jun [5 ]
Treutlein, Herbert R. [5 ,8 ]
Hook, Jeff [4 ]
Hardeman, Edna C. [4 ]
Gunning, Peter W. [4 ]
Fodde, Riccardo [1 ]
机构
[1] Erasmus Univ, Med Ctr, Dept Pathol, Rotterdam, Netherlands
[2] Inst Curie, Lab Genet & Dev Biol, Paris, France
[3] Erasmus Univ, Med Ctr, Dept Med Oncol, Rotterdam, Netherlands
[4] Univ New South Wales, Fac Med & Hlth, Sch Biomed Sci, Sydney, NSW, Australia
[5] Computist Bionanotech, Scoresby, Vic 3179, Australia
[6] Elisabeth TweeSteden Ziekenhuis ETZ, Tilburg, Netherlands
[7] Victor Chang Cardiac Res Inst, Darlinghurst, NSW, Australia
[8] Scolexia Pty Ltd, Moonee Ponds, Vic 3039, Australia
基金
英国医学研究理事会;
关键词
ACTIN CYTOSKELETON; GENE; SUPPRESSOR; INHIBITORS; TARGETS; DESIGN; METHYLATION; EXPRESSION; INSIGHTS; BIOLOGY;
D O I
10.1038/s41418-024-01267-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Phenotypic plasticity, defined as the ability of individual cells with stable genotypes to exert different phenotypes upon exposure to specific environmental cues, represent the quintessential hallmark of the cancer cell en route from the primary lesion to distant organ sites where metastatic colonization will occur. Phenotypic plasticity is driven by a broad spectrum of epigenetic mechanisms that allow for the reversibility of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions (EMT/MET). By taking advantage of the co-existence of epithelial and quasi-mesenchymal cells within immortalized cancer cell lines, we have analyzed the role of EMT-related gene isoforms in the regulation of epithelial mesenchymal plasticity (EMP) in high grade serous ovarian cancer. When compared with colon cancer, a distinct spectrum of downstream targets characterizes quasi-mesenchymal ovarian cancer cells, likely to reflect the different modalities of metastasis formation between these two types of malignancy, i.e. hematogenous in colon and transcoelomic in ovarian cancer. Moreover, upstream RNA-binding proteins differentially expressed between epithelial and quasi-mesenchymal subpopulations of ovarian cancer cells were identified that underlie differential regulation of EMT-related isoforms. In particular, the up- and down-regulation of RBM24 and ESRP1, respectively, represent a main regulator of EMT in ovarian cancer cells. To validate the functional and clinical relevance of our approach, we selected and functionally analyzed the Tropomyosin 1 gene (TPM1), encoding for a protein that specifies the functional characteristics of individual actin filaments in contractile cells, among the ovarian-specific downstream AS targets. The low-molecular weight Tpm1.8/9 isoforms are specifically expressed in patient-derived ascites and promote invasion through activation of EMT and Wnt signaling, together with a broad spectrum of inflammation-related pathways. Moreover, Tpm1.8/9 expression confers resistance to taxane- and platinum-based chemotherapy. Small molecule inhibitors that target the Tpm1 isoforms support targeting Tpm1.8/9 as therapeutic targets for the development of future tailor-made clinical interventions.
引用
收藏
页码:511 / 523
页数:13
相关论文
共 68 条
  • [21] GSVA: gene set variation analysis for microarray and RNA-Seq data
    Haenzelmann, Sonja
    Castelo, Robert
    Guinney, Justin
    [J]. BMC BIOINFORMATICS, 2013, 14
  • [22] Integrated analysis of multimodal single-cell data
    Hao, Yuhan
    Hao, Stephanie
    Andersen-Nissen, Erica
    Mauck, William M. I. I. I. I. I. I.
    Zheng, Shiwei
    Butler, Andrew
    Lee, Maddie J.
    Wilk, Aaron J.
    Darby, Charlotte
    Zager, Michael
    Hoffman, Paul
    Stoeckius, Marlon
    Papalexi, Efthymia
    Mimitou, Eleni P.
    Jain, Jaison
    Srivastava, Avi
    Stuart, Tim
    Fleming, Lamar M.
    Yeung, Bertrand
    Rogers, Angela J.
    McElrath, Juliana M.
    Blish, Catherine A.
    Gottardo, Raphael
    Smibert, Peter
    Satija, Rahul
    [J]. CELL, 2021, 184 (13) : 3573 - +
  • [23] Hardeman E, 2022, Patent, Patent No. [2020037079A1, 2020037079]
  • [24] Hardeman E, 2021, Patent, Patent No. 2021072487
  • [25] Impact of the actin cytoskeleton on cell development and function mediated via tropomyosin isoforms
    Hardeman, Edna C.
    Bryce, Nicole S.
    Gunning, Peter W.
    [J]. SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2020, 102 : 122 - 131
  • [26] A single-cell landscape of high-grade serous ovarian cancer
    Izar, Benjamin
    Tirosh, Itay
    Stover, Elizabeth H.
    Wakiro, Isaac
    Cuoco, Michael S.
    Alter, Idan
    Rodman, Christopher
    Leeson, Rachel
    Su, Mei-Ju
    Shah, Parin
    Iwanicki, Marcin
    Walker, Sarah R.
    Kanodia, Abhay
    Melms, Johannes C.
    Mei, Shaolin
    Lin, Jia-Ren
    Porter, Caroline B. M.
    Slyper, Michal
    Waldman, Julia
    Jerby-Arnon, Livnat
    Ashenberg, Orr
    Brinker, Titus J.
    Mills, Caitlin
    Rogava, Meri
    Vigneau, Sebastien
    Sorger, Peter K.
    Garraway, Levi A.
    Konstantinopoulos, Panagiotis A.
    Liu, Joyce F.
    Matulonis, Ursula
    Johnson, Bruce E.
    Rozenblatt-Rosen, Orit
    Rotem, Asaf
    Regev, Aviv
    [J]. NATURE MEDICINE, 2020, 26 (08) : 1271 - +
  • [27] Molecular integration of the anti-tropomyosin compound ATM-3507 into the coiled coil overlap region of the cancer-associated Tpm3.1
    Janco, Miro
    Rynkiewicz, Michael J.
    Li, Liang
    Hook, Jeff
    Eiffe, Eleanor
    Ghosh, Anita
    Bocking, Till
    Lehman, William J.
    Hardeman, Edna C.
    Gunning, Peter W.
    [J]. SCIENTIFIC REPORTS, 2019, 9 (1) : 11262
  • [28] Ovarian cancer
    Jayson, Gordon C.
    Kohn, Elise C.
    Kitchener, Henry C.
    Ledermann, Jonathan A.
    [J]. LANCET, 2014, 384 (9951) : 1376 - 1388
  • [29] Analysis and design of RNA sequencing experiments for identifying isoform regulation
    Katz, Yarden
    Wang, Eric T.
    Airoldi, Edoardo M.
    Burge, Christopher B.
    [J]. NATURE METHODS, 2010, 7 (12) : 1009 - U101
  • [30] Meeting the challenge of ascites in ovarian cancer: new avenues for therapy and research
    Kipps, Emma
    Tan, David S. P.
    Kaye, Stan B.
    [J]. NATURE REVIEWS CANCER, 2013, 13 (04) : 273 - 282