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MSK1 Regulates Luminal Cell Differentiation and Metastatic Dormancy in ER+ Breast Cancer

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MSK1 Regulates Luminal Cell Differentiation and Metastatic Dormancy in ER+ Breast Cancer ARTICLES https://doi.org/10.1038/s41556-017-0021-z MSK1 regulates luminal cell differentiation and metastatic dormancy in ER+ breast cancer Sylwia Gawrzak1, Lorenzo Rinaldi1, Sara Gregorio1, Enrique J. Arenas1, Fernando Salvador1, Jelena Urosevic1,2, Cristina Figueras-Puig1, Federico Rojo2,3,4, Ivan del Barco Barrantes1, Juan Miguel Cejalvo1,5, Marta Palafox6, Marc Guiu1,2, Antonio Berenguer-Llergo 7, Aikaterini Symeonidi1, Anna Bellmunt1, Daniela Kalafatovic1, Anna Arnal-Estapé1,20, Esther Fernández1, Barbara Müllauer1, Rianne Groeneveld1, Konstantin Slobodnyuk1, Camille Stephan-Otto Attolini 7, Cristina Saura8,9, Joaquín Arribas2,9,10,11, Javier Cortes9,12, Ana Rovira3,13, Montse Muñoz5,14, Ana Lluch2,15,16,17, Violeta Serra2,6, Joan Albanell2,3,13,18, Aleix Prat5,14, Angel R. Nebreda1,11, Salvador Aznar Benitah 1,11 and Roger R. Gomis 1,2,11,19* For many patients with breast cancer, symptomatic bone metastases appear after years of latency. How micrometastatic lesions remain dormant and undetectable before initiating colonization is unclear. Here, we describe a mechanism involved in bone metastatic latency of oestrogen receptor-positive (ER+) breast cancer. Using an in vivo genome-wide short hairpin RNA screening, we identified the kinase MSK1 as an important regulator of metastatic dormancy in breast cancer. In patients with ER+ breast cancer, low MSK1 expression associates with early metastasis. We show that MSK1 downregulation impairs the dif- ferentiation of breast cancer cells, increasing their bone homing and growth capacities. MSK1 controls the expression of genes required for luminal cell differentiation, including the GATA3 and FOXA1 transcription factors, by modulating their promoter chromatin status. Our results indicate that MSK1 prevents metastatic progression of ER+ breast cancer, suggesting that strati- fying patients with breast cancer as high or low risk for early relapse based on MSK1 expression could improve prognosis. etastasis in breast cancer generally manifests asynchro- models, and even less so in a clinical context. Metastatic lesions nously with the primary tumour, with different timelines that originate from DTCs or micrometastases after a period of to clinical detection of symptoms. This time depends on latency retain the vast majority of genetic and molecular altera- M 1 3 the volume, stage and molecular subtype of the primary tumour . tions (80–85%) initially described at the primary site . However, However, luminal tumours, which usually express oestrogen recep- discordance in the intrinsic or hormonal status of breast can- tor (ER), may recur after a long period of time, characterized by cer subtypes has been reported in metastatic progression—for the absence of symptoms. The capacity of micrometastases and/or instance, luminal/HER2-negative (HER2–) tumours acquire a disseminated tumour cells (DTCs) in the bone marrow to main- luminal B or HER2-enriched profile during metastatic progres- tain themselves at low numbers after primary tumour resection is sion3,4. This suggests that important, but subtle, loss of molecular critical for tumour latency and may explain how disease can resist differentiation properties arise during metastatic progression, and treatment and reappear after long asymptomatic periods. Several that dormancy may be an endowed state. We aimed to distinguish clinical trials have revealed that the presence of circulating tumour whether these differentiation changes are passengers during the cell (CTC) counts in blood has prognostic relevance with respect to tumour evolution or, alternatively, if they have functional conse- metastasis progression2. This observation suggests that dormancy quences for latency and overt metastasis. or quiescence of a solitary cell is not a unique feature of latent meta- To this end, we performed an in vivo loss-of-function, static lesions, and that a combination of proliferative and apoptotic genome-wide short hairpin RNA (shRNA) screening to identify activities is required to sustain the release of CTCs. genes involved in breast cancer latency, using an experimental Until now, the mechanisms enabling breast cancer cells to exit mouse model based on human ER-positive (ER+) breast cancer from latency have been only poorly understood in preclinical cells that are moderately metastatic for bone. After injection into 1Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. 2CIBERONC, Madrid, Spain. 3Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. 4Pathology Department, IIS-Fundación Jimenez Diaz, Madrid, Spain. 5Translational Genomics and Targeted Therapeutics, Institut d’Investigacions Biomèdiques Pi i Sunyer-IDIBAPS, Barcelona, Spain. 6Experimental Therapeutics, Vall d’Hebron Insitute of Oncology, Barcelona, Spain. 7Biostatistics and Bioinformatics Unit, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. 8Department of Oncology, Vall d’Hebrón University Hospital, Barcelona, Spain. 9Vall d’Hebron Institute of Oncology, Barcelona, Spain. 10Universitat Autònoma de Barcelona, Bellaterra, Spain. 11ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain. 12Ramon y Cajal University Hospital, Madrid, Spain. 13Medical Oncology Service, Hospital del Mar, Barcelona, Spain. 14Department of Oncology, Hospital Clinic de Barcelona, Barcelona, Spain. 15Department of Oncology and Hematology, Hospital Clínico Universitario, Valencia, Spain. 16University of Valencia, Valencia, Spain. 17INCLIVA, Instituto de Investigación Sanitaria, Valencia, Spain. 18Universitat Pompeu Fabra, Barcelona, Spain. 19Universitat de Barcelona, Barcelona, Spain. Present address: 20Department of Pathology, Yale University School of Medicine, Yale, CT, USA. *e-mail: [email protected] NATURE CELL BiologY | VOL 20 | FEBRUARY 2018 | 211–221 | www.nature.com/naturecellbiology 211 © 2018 Nature America Inc., part of Springer Nature. All rights reserved. ARTICLES NATURE CELL BIOLOGY immunodeficient mice, these cells form latent micrometastatic slow tumour cell proliferation and controlled apoptosis keeping the bone lesions for extended periods of time before causing overt mass at a steady size (Fig. 1h). metastasis. These studies identified mitogen- and stress-activated kinase 1 (MSK1) as an important regulator of metastatic latency. MSK1 regulates tumour mass dormancy in ER+ breast can- Clinically, low MSK1 expression associates with early relapse in cer, and its high expression associates with late metastases in patients with ER+ breast cancer. At the molecular level, reduced patients with ER+ breast cancer. We next performed an unbi- MSK1 expression causes chromatin remodelling, which decreases ased, genome-wide shRNA screening to identify regulators of differentiation traits (including reduced expression of the genes tumour mass dormancy in ER+ breast cancer (Fig. 2a). We used encoding GATA3 and FOXA1 transcription factors) and facili- a whole-genome human shRNA lentiviral library divided into 10 tates bone colonization by cells in micrometastatic lesions. pools, each containing 8,000 shRNAs. Numerous distinct shRNAs (4–5) that target each of the 16,019 human genes were included Results in the screen and scrutinized to exclude off-targets (Fig. 2a), Latent tumour mass bone metastasis model in ER+ breast can- and 0.4 viral multiplicity of infection was used to ensure one inte- cer. To test whether dormancy is the default state in disseminated grant per cell. Infected cells were selected with puromycin and luminal breast cancer cells and micrometastatic lesions, we devel- insertion was confirmed by PCR (Fig. 2b), and each cell pool oped an experimental latency bone metastasis model and designed was injected into the left ventricle of ten mice. The cells that a systemic and unbiased experimental approach to identify genes expanded and caused symptomatic metastasis were green fluo- that regulate dormancy. High-performance, live-animal imaging rescent protein (GFP) sorted, and the integrated shRNAs were techniques allowed us to track and selectively isolate dormant bone sequenced (Fig. 2a). Using the BLI method, a fourfold increase in metastatic (DBM) T47D luminal (ER+) breast cancer cell deriva- the number of overt metastases was detected in the shRNA pools tives that, despite their reproducibly long latency phase, form bone compared to control cells at a 4-month post-injection analysis lesions after injection into the left ventricle of mice (Fig. 1a and (Fig. 2c–e). Retrieved sequences were then weighted based on Supplementary Fig. 1a,b). Contrary to previously reported breast their representation in metastatic lesions and associated with cancer experimental metastasis models selected for bone tropism5 their target gene (Supplementary Table 2). shRNAs represented by (Supplementary Fig. 1c,d), only a small fraction of animals devel- 10–300 copies in the cell pool prior to inoculation were selected, oped an overt lesion at late time points. These cells showed three and genes whose silencing was expected to either reduce cell death distinct growth phases: homing (n =​ 8 out of 12), latency (n = 5 out or enhance proliferation were omitted (Fig. 2f); this resulted in of 12) and symptomatic metastasis (n =​ 2 out of 12) (Fig. 1a and a short-list of 322 genes (Fig. 2g). The RPS6KA5 gene, which Supplementary Fig. 1b). We visualized metastatic cells in the mouse encodes
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