title: BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance.
abstract: Melanoma can switch between proliferative and invasive states, which have identifying gene expression signatures that correlate with good and poor prognosis, respectively. However, the mechanisms controlling these signatures are poorly understood. In this study, we identify BMI1 as a key determinant of melanoma metastasis by which its overexpression enhanced and its deletion impaired dissemination. Remarkably, in this tumor type, BMI1 had no effect on proliferation or primary tumor growth but enhanced every step of the metastatic cascade. Consistent with the broad spectrum of effects, BMI1 activated widespread gene expression changes, which are characteristic of melanoma progression and also chemoresistance. Accordingly, we showed that up-regulation or down-regulation of BMI1 induced resistance or sensitivity to BRAF inhibitor treatment and that induction of noncanonical Wnt by BMI1 is required for this resistance. Finally, we showed that our BMI1-induced gene signature encompasses all of the hallmarks of the previously described melanoma invasive signature. Moreover, our signature is predictive of poor prognosis in human melanoma and is able to identify primary tumors that are likely to become metastatic. These data yield key insights into melanoma biology and establish BMI1 as a compelling drug target whose inhibition would suppress both metastasis and chemoresistance of melanoma.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts 02139, USA;
authors.forename: Roberta
authors.initials: R
authors.lastname: Ferretti
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts 02139, USA;
authors.forename: Arjun
authors.initials: A
authors.lastname: Bhutkar
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Molly C
authors.initials: MC
authors.lastname: McNamara
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Lees
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D012878:Skin Neoplasms; D000096142:Cutaneous Malignant Melanoma
chemical_list: D000970:Antineoplastic Agents; C069077:BMI1 protein, human; D063150:Polycomb Repressive Complex 1; D048493:Proto-Oncogene Proteins B-raf
keywords: BMI1; invasive signature; melanoma; metastases; therapeutic resistance