PT  - JOURNAL ARTICLE
AU  - Nair, Praful R.
AU  - Danilova, Ludmila
AU  - Gómez-de-Mariscal, Estibaliz
AU  - Kim, Dongjoo
AU  - Fan, Rong
AU  - Muñoz-Barrutia, Arrate
AU  - Fertig, Elana J.
AU  - Wirtz, Denis
TI  - MLL1 regulates cytokine-driven cell migration and metastasis
AID  - 10.1101/2022.10.18.512715
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.10.18.512715
4099  - http://biorxiv.org/content/early/2022/10/19/2022.10.18.512715.short
4100  - http://biorxiv.org/content/early/2022/10/19/2022.10.18.512715.full
AB  - Cell migration is a critical requirement for cancer metastasis. Cytokine production and its role in cancer cell migration have been traditionally associated with immune cells in the tumor microenvironment. MLL1 is a histone methyltransferase that controls 3D cell migration via the secretion of cytokines, IL-6 and TGF-β1, by the cancer cells themselves. In vivo, MLL1 depletion reduced metastatic burden and prolonged survival. MLL1 exerts its effects with its scaffold protein, Menin. Mechanistically, the MLL1-Menin interaction controls actin filament assembly via the IL-6/pSTAT3/Arp3 axis and acto-myosin contractility via the TGF-β1/Gli2/ROCK1/2/pMLC2 axis, which regulate dynamic protrusion generation and 3D cell migration. MLL1 also regulates cell proliferation via mitosis-based and cell cycle-related pathways. Combining an MLL1-Menin inhibitor with Paclitaxel, a standard chemotherapeutic, abrogated tumor growth and metastasis in a syngeneic model. These results highlight the potential of targeting the MLL1 in metastasis prevention and its potential to be combined with currently administered chemotherapeutics.Statement of Significance We identify MLL1 as being vital to metastasis, which causes the vast majority of cancer-related deaths. MLL1 controls cell migration, a requirement for metastasis, by regulating the secretion of cytokines. MLL1 inhibition lowers metastatic burden independent of its impact on primary tumor growth, highlighting its anti-metastatic potential in TNBC.Competing Interest StatementOne of the authors, R.F., is a shareholder in AtlasXomics. All other authors declare no competing interests.CMConditioned mediumEMTEpithelial to mesenchymal transitionGSEAGene Set Enrichment AnalysisH3K4Histone 3 Lysine (K) 4HDHigh density (100 cells/mm3)HRHazard RatioILInterleukinLDLow density (10 cells/mm3)MLCMyosin Light ChainNDNot detectedpMLC2phospho-Myosin Light Chain 2MLL1Mixed Lineage LeukemiaMLL iMLL1-Menin interaction inhibitor/inhibitionMSDMean squared displacementSC(Non-targeting) Scrambled shRNA ControlTCGAThe Cancer Genome AtlasTGFTransforming Growth FactorTCGAThe Cancer Genome AtlasTNBCTriple negative breast cancerTSSTranscription start siteWTWild-type