Stabilizing vimentin phosphorylation inhibits stem-like cell properties and metastasis of hybrid epithelial/mesenchymal carcinomas
Nick A. Kuburich,
Petra den Hollander,
Maria Castaneda,
Mika Pietilä,
Ximing Tang,
Harsh Batra,
Francisco Martínez-Peña,
Tanvi H. Visal,
Tieling Zhou,
Breanna R. Demestichas,
Ritesh V. Dontula,
Jojo Y. Liu,
Joanna Joyce Maddela,
Reethi S. Padmanabhan,
Lan Thi Hanh Phi,
Matthew J. Rosolen,
Thiru Sabapathy,
Dhiraj Kumar,
Filippo G. Giancotti,
Luke L. Lairson,
Maria Gabriela Raso,
Rama Soundararajan,
Sendurai A. Mani
Affiliations
Nick A. Kuburich
Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
Petra den Hollander
Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
Maria Castaneda
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Mika Pietilä
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Janssen Pharmaceutical Companies of Johnson & Johnson, Espoo, Uusimaa, Finland
Ximing Tang
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Harsh Batra
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Francisco Martínez-Peña
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
Tanvi H. Visal
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Tieling Zhou
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Breanna R. Demestichas
Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
Ritesh V. Dontula
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jojo Y. Liu
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Joanna Joyce Maddela
Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
Reethi S. Padmanabhan
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Lan Thi Hanh Phi
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Matthew J. Rosolen
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Thiru Sabapathy
Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
Dhiraj Kumar
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Cancer Metastasis Initiative, Herbert Irving Comprehensive Cancer Center, Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
Filippo G. Giancotti
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Cancer Metastasis Initiative, Herbert Irving Comprehensive Cancer Center, Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
Luke L. Lairson
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
Maria Gabriela Raso
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Rama Soundararajan
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Sendurai A. Mani
Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Corresponding author
Summary: Epithelial-mesenchymal transition (EMT) empowers epithelial cells with mesenchymal and stem-like attributes, facilitating metastasis, a leading cause of cancer-related mortality. Hybrid epithelial-mesenchymal (E/M) cells, retaining both epithelial and mesenchymal traits, exhibit heightened metastatic potential and stemness. The mesenchymal intermediate filament, vimentin, is upregulated during EMT, enhancing the resilience and invasiveness of carcinoma cells. The phosphorylation of vimentin is critical to its structure and function. Here, we identify that stabilizing vimentin phosphorylation at serine 56 induces multinucleation, specifically in hybrid E/M cells with stemness properties but not epithelial or mesenchymal cells. Cancer stem-like cells are especially susceptible to vimentin-induced multinucleation relative to differentiated cells, leading to a reduction in self-renewal and stemness. As a result, vimentin-induced multinucleation leads to sustained inhibition of stemness properties, tumor initiation, and metastasis. These observations indicate that a single, targetable phosphorylation event in vimentin is critical for stemness and metastasis in carcinomas with hybrid E/M properties.
