MLL1 regulates cytokine-driven cell migration and metastasis-Reference-Cited by-同舟云学术

MLL1 regulates cytokine-driven cell migration and metastasis

Published:2024-03-15 Issue:11 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Nair Praful R.¹^ORCID,Danilova Ludmila²^ORCID,Gómez-de-Mariscal Estibaliz³⁴^ORCID,Kim Dongjoo⁵^ORCID,Fan Rong⁵^ORCID,Muñoz-Barrutia Arrate³^ORCID,Fertig Elana J.²⁶⁷^ORCID,Wirtz Denis¹²⁸⁹^ORCID

Affiliation:

1. Institute for Nanobiotechnology, The Johns Hopkins University, Baltimore, MD 21218, USA.

2. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

3. Bioengineering and Aerospace Engineering Department, Universidad Carlos III de Madrid, 28911 Leganés, and Instituto de Investigación Sanitaria Gregorio Marañón, 28007 Madrid, Spain.

4. Optical Cell Biology Group, Instituto Gulbenkian de Ciência, R. Q.ta Grande 6 2780, 2780-156 Oeiras, Portugal.

5. Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.

6. Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA.

7. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA.

8. Department of Chemical and Biomolecular Engineering, Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, MD 21218, USA.

9. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Abstract

Cell migration is a critical contributor to metastasis. Cytokine production and its role in cancer cell migration have been traditionally associated with immune cells. We find that the histone methyltransferase Mixed-Lineage Leukemia 1 (MLL1) controls 3D cell migration via cytokines, IL-6, IL-8, and TGF-β1, secreted by the cancer cells themselves. MLL1, with its scaffold protein Menin, controls actin filament assembly via the IL-6/8/pSTAT3/Arp3 axis and myosin contractility via the TGF-β1/Gli2/ROCK1/2/pMLC2 axis, which together regulate dynamic protrusion generation and 3D cell migration. MLL1 also regulates cell proliferation via mitosis-based and cell cycle–related pathways. Mice bearing orthotopic MLL1-depleted tumors exhibit decreased lung metastatic burden and longer survival. MLL1 depletion leads to lower metastatic burden even when controlling for the difference in primary tumor growth rates. Combining MLL1-Menin inhibitor with paclitaxel abrogates tumor growth and metastasis, including preexistent metastasis. These results establish MLL1 as a potent regulator of cell migration and highlight the potential of targeting MLL1 in patients with metastatic disease.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adk0785

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