title: Cell crowding induces interferon regulatory factor 9, which confers resistance to chemotherapeutic drugs.
abstract: The mechanism of multicellular drug resistance, defined as the reduced efficacy of chemotherapeutic drugs in solid tumors is incompletely understood. Here we report that colon carcinoma cells cultured as 3D microtissues (spheroids) display dramatic increases in the expression of a subset of type I interferon-(IFN)-stimulated genes (ISGs). A similar gene signature was associated previously with resistance to radiation and chemotherapy, prompting us to examine the underlying biological mechanisms. Analysis of spheroids formed by different tumor cell lines and studies using knock-down of gene expression showed that cell crowding leads to the induction of IFN regulatory factor-9 (IRF9) which together with STAT2 and independently of IFNs, is necessary for ISG upregulation. Increased expression of IRF9 alone was sufficient to induce the ISG subset in monolayer cells and to confer increased resistance to clinically used cytotoxic drugs. Our data reveal a novel mechanism of regulation of a subset of ISGs, leading to drug resistance in solid tumors.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, 17176, Stockholm, Sweden.
authors.forename: Iryna
authors.initials: I
authors.lastname: Kolosenko
authors.forename: Mårten
authors.initials: M
authors.lastname: Fryknäs
authors.forename: Sofi
authors.initials: S
authors.lastname: Forsberg
authors.forename: Per
authors.initials: P
authors.lastname: Johnsson
authors.forename: HyeonJoo
authors.initials: H
authors.lastname: Cheon
authors.forename: Elise G
authors.initials: EG
authors.lastname: Holvey-Bates
authors.forename: Elin
authors.initials: E
authors.lastname: Edsbäcker
authors.forename: Paola
authors.initials: P
authors.lastname: Pellegrini
authors.forename: Hanif
authors.initials: H
authors.lastname: Rassoolzadeh
authors.forename: Slavica
authors.initials: S
authors.lastname: Brnjic
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
authors.forename: Dan
authors.initials: D
authors.lastname: Grandér
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
authors.forename: Katja Pokrovskaja
authors.initials: KP
authors.lastname: Tamm
authors.forename: Angelo
authors.initials: A
authors.lastname: De Milito
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002450:Cell Communication; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics* / Q000378:metabolism; D007372:Interferons / Q000502:physiology; D050795:STAT2 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D000970:Antineoplastic Agents; C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D007372:Interferons
keywords: IRF9; STAT transcription factors; chemoresistance; interferon-stimulated genes; multicellular spheroids