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Cited by 0Wnt/β-catenin signaling in development and cancerMechanisms of cancer metastasisCancer Cells and Metastasis

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ROME, an Ancient Gene with a Novel Function in Vertebrates, Is a Key Modulator of Embryonal Development and Cancer Metastasis

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Molotkova, Anna, Deniz, Emre, Swift, Matthew, Glasgow, Eric, Ma, Junfeng, Petro, Jeffrey A., Frye, Isabel, Ozdemirli, Metin, Pesic, Dusan, Ahern, Gerard P., Suter, Robert K., Tiwari, Purushottam B., Shlien, Adam, Toretsky, Jeffrey, Üren, Aykut·2026·Cancer Research Communications
DOI 10.1158/2767-9764.crc-26-0068

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Abstract

INAFM2, the human homolog of the Drosophila inaF, is a predicted membrane protein with no known function in vertebrates. Through an in vivo genome-wide transcriptional activation screen, we uncovered INAFM2 as a potent driver of metastasis, leading us to propose naming the vertebrate gene and its protein product ROME (regulator of metastasis). We discovered ROME’s subcellular localization, posttranslational modifications, and transcriptional profiles related to its expression. ROME negatively regulates the canonical Wnt pathway by directly binding to β-catenin. Blocking rome expression in zebrafish embryos results in severe developmental defects and early mortality, which can be reversed by inhibiting the canonical Wnt pathway. Notably, we demonstrate that ROME expression regulates human cancer cell motility and invasion in vitro and metastasis in vivo in both zebrafish and immunodeficient mice via tail vein and orthotopic injection models. ROME-mediated increase in cancer cell intravasation is dependent on its direct interaction with vimentin. Furthermore, we show that elevated ROME expression correlates with poorer patient survival in multiple human cancers. Taken together, this is the first report of the vertebrate ROME gene producing a biologically active plasma membrane glycoprotein that is critical for normal development and metastasis. Significance: This is the first report of a detailed characterization of the molecular features of ROME (INAFM2) protein in mammalian cells and its biochemical and biological functions related to vertebrate development and cancer metastasis.

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Metadata

Authors
Molotkova, A., Deniz, E., Swift, M., Glasgow, E., Ma, J., Petro, J. A., Frye, I., Ozdemirli, M., Pesic, D., Ahern, G. P., Suter, R. K., Tiwari, P. B., Shlien, A., Toretsky, J., & Üren, A.
Affiliations
  • Georgetown University Medical Center (US)
  • Georgetown University Medical Center 2 Department of Pathology, , Washington, District of Columbia.
  • Hospital for Sick Children (CA)
Corresponding author
Üren, Aykut
ORCID
Venue
Cancer Research Communications
Publisher
American Association for Cancer Research (AACR)
Published
2026-03-01
Volume
6
Issue
3
Pages
477-499
ISSN
2767-9764 (ISSN-L)
DOI
10.1158/2767-9764.crc-26-0068
OpenAlex
W7128207529
Cited by
0
References
4
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Research Communications (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
  • Children’s Cancer Foundation
  • National Cancer Institute (F30CA287917, R01CA233619-01A1)
  • Hyundai Hope On Wheels
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
Rome, metastasis, Wnt/β-catenin signaling, embryonic development, tumor cell motility, tumor invasion, intravasation, vimentin, plasma membrane glycoproteins, zebrafish, patient survival
MeSH terms
Animals, Cell Movement, Humans, Membrane Proteins, Neoplasm Metastasis, Neoplasms, Vertebrates, Zebrafish, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Embryonic Development, beta Catenin, Mice, Wnt Signaling Pathway

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