Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2017

Open Access 01-12-2017 | Review

Role of protein kinases CK1α and CK2 in multiple myeloma: regulation of pivotal survival and stress-managing pathways

Authors: Sabrina Manni, Marilena Carrino, Francesco Piazza

Published in: Journal of Hematology & Oncology | Issue 1/2017

Login to get access

Abstract

Multiple myeloma (MM) is a malignant tumor of transformed plasma cells. MM pathogenesis is a multistep process. This cancer can occur de novo (rarely) or it can develop from monoclonal gammopathy of undetermined significance (most of the cases). MM can be asymptomatic (smoldering myeloma) or clinically active. Malignant plasma cells exploit intrinsic and extrinsic bone marrow microenvironment-derived growth signals. Upregulation of stress-coping pathways is also instrumental to maintain MM cell growth. The phylogenetically related Ser/Thr kinases CSNK1A1 (CK1α) and CSNK2 (CK2) have recently gained a growing importance in hematologic malignancies arising both from precursors and from mature blood cells. In multiple myeloma, CK1α or CK2 sustain oncogenic cascades, such as the PI3K/AKT, JAK/STAT, and NF-κB, as well as propel stress-related signaling that help in coping with different noxae. Data also suggest that these kinases modulate the delivery of growth factors and cytokines from the bone marrow stroma. The “non-oncogene addiction” phenotype generated by the increased activity of CK1α and CK2 in multiple myeloma contributes to malignant plasma cell proliferation and survival and represents an Achilles’ heel for the activity of small ATP competitive CK1α or CK2 inhibitors.
Literature
1.
2.
Podar K, Chauhan D, Anderson KC. Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia. 2009;23:10–24.CrossRefPubMed
3.
Manier S, Sacco A, Leleu X, Ghobrial IM, Roccaro AM. Bone marrow microenvironment in multiple myeloma progression. J Biomed Biotechnol. 2012;2012:157496.CrossRefPubMedPubMedCentral
4.
Bahlis NP, NJ. Targeting of adhesion molecules as a therapeutic strategy in multiple myeloma. Curr Cancer Drug Targets. 2012;12:776–96.CrossRefPubMed
5.
Hussein MA. Multiple myeloma: most common end-organ damage and management. J Natl Compr Canc Netw. 2007;5:170–8.CrossRefPubMed
6.
7.
8.
Manni S, Toscani D, Mandato E, Brancalion A, Quotti Tubi L, Macaccaro P, et al. Bone marrow stromal cell-fueled multiple myeloma growth and osteoclastogenesis are sustained by protein kinase CK2. Leukemia. 2014;28:2094–7.CrossRefPubMed
9.
Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Kung AL, Davies FE, et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood. 2006;107:1092–100.CrossRefPubMedPubMedCentral
10.
Cea M, Cagnetta A, Adamia S, Acharya C, Tai Y-T, Fulciniti M, et al. Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells. Blood. 2016;127:1138–50.CrossRefPubMedPubMedCentral
11.
Ocio EM, San Miguel JF. The DAC system and associations with multiple myeloma. Investig New Drugs. 2010;28(Suppl 1):S28–35.CrossRef
12.
13.
Cottini F, Hideshima T, Suzuki R, Tai Y-T, Bianchini G, Richardson PG, et al. Synthetic lethal approaches exploiting DNA damage in aggressive myeloma. Cancer Discov. 2015;5:972–87.CrossRefPubMedPubMedCentral
14.
15.
Manni S, Brancalion A, Tubi LQ, Colpo A, Pavan L, Cabrelle A, et al. Protein kinase CK2 protects multiple myeloma cells from ER stress-induced apoptosis and from the cytotoxic effect of HSP90 inhibition through regulation of the unfolded protein response. Clin Cancer Res. 2012;18:1888–900.CrossRefPubMed
16.
Manni S, Brancalion A, Mandato E, Quotti Tubi L, Tubi LQ, Colpo A, et al. Protein kinase CK2 inhibition down modulates the NF-kappaB and STAT3 survival pathways, enhances the cellular proteotoxic stress and synergistically boosts the cytotoxic effect of bortezomib on multiple myeloma and mantle cell lymphoma cells. PLoS One. 2013;8:e75280.CrossRefPubMedPubMedCentral
17.
Manni S, Carrino M, Manzoni M, Gianesin K, Nunes SC, Costacurta M, et al. Inactivation of CK1alpha in multiple myeloma empowers drug cytotoxicity by affecting AKT and beta-catenin survival signaling pathways. Oncotarget. 2017;8:14604–19.CrossRefPubMedPubMedCentral
18.
Knippschild U, Gocht A, Wolff S, Huber N, Lohler J, Stoter M. The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. Cell Signal. 2005;17:675–89.CrossRefPubMed
19.
Knippschild U, Kruger M, Richter J, Xu P, Garcia-Reyes B, Peifer C, et al. The CK1 family: contribution to cellular stress response and its role in carcinogenesis. Front Oncol. 2014;4:96.CrossRefPubMedPubMedCentral
20.
Elyada E, Pribluda A, Goldstein RE, Morgenstern Y, Brachya G, Cojocaru G, et al. CKIalpha ablation highlights a critical role for p53 in invasiveness control. Nature. 2011;470:409–13.CrossRefPubMed
21.
Pribluda A, Elyada E, Wiener Z, Hamza H, Goldstein RE, Biton M, et al. A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell. 2013;24:242–56.CrossRefPubMed
22.
Jaras M, Miller PG, Chu LP, Puram RV, Fink EC, Schneider RK, et al. Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. J Exp Med. 2014;211:605–12.CrossRefPubMedPubMedCentral
23.
Cheong JK, Zhang F, Chua PJ, Bay BH, Thorburn A, Virshup DM. Casein kinase 1alpha-dependent feedback loop controls autophagy in RAS-driven cancers. J Clin Invest. 2015;125:1401–18.CrossRefPubMedPubMedCentral
24.
Bidere N, Ngo VN, Lee J, Collins C, Zheng L, Wan F, et al. Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival. Nature. 2009;458:92–6.CrossRefPubMed
25.
26.
Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, Kamura T, et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet. 2013;45:860–7.CrossRefPubMed
27.
Okerberg ES, Hainley A, Brown H, Aban A, Alemayehu S, Shih A, et al. Identification of a tumor specific, active-site mutation in casein kinase 1alpha by chemical proteomics. PLoS One. 2016;11:e0152934.CrossRefPubMedPubMedCentral
28.
Dulak AM, Stojanov P, Peng S, Lawrence MS, Fox C, Stewart C, et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet. 2013;45:478–86.CrossRefPubMedPubMedCentral
29.
Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J-I, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet. 2015;47:1304–15.CrossRefPubMed
30.
Schneider RK, Adema V, Heckl D, Jaras M, Mallo M, Lord AM, et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell. 2014;26:509–20.CrossRefPubMedPubMedCentral
31.
Hu Y, Song W, Cirstea D, Lu D, Munshi NC, Anderson KC. CSNK1alpha1 mediates malignant plasma cell survival. Leukemia. 2015;29:474–82.CrossRefPubMed
32.
33.
Gowda C, Song C, Kapadia M, Payne JL, Hu T, Ding Y, et al. Regulation of cellular proliferation in acute lymphoblastic leukemia by Casein Kinase II (CK2) and Ikaros. Adv Biol Regul. 2017;63:71–80.CrossRefPubMed
34.
Piazza F, Manni S, Ruzzene M, Pinna LA, Gurrieri C, Semenzato G. Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways. Leukemia. 2012;26:1174–9.CrossRefPubMed
35.
Piazza F, Manni S, Semenzato G. Novel players in multiple myeloma pathogenesis: role of protein kinases CK2 and GSK3. Leuk Res. 2013;37:221–7.CrossRefPubMed
36.
Meggio F, Pinna LA. One-thousand-and-one substrates of protein kinase CK2? FASEB J. 2003;17:349–68.CrossRefPubMed
37.
Di Maira G, Salvi M, Arrigoni G, Marin O, Sarno S, Brustolon F, et al. Protein kinase CK2 phosphorylates and upregulates Akt/PKB. Cell Death Differ. 2005;12:668–77.CrossRefPubMed
38.
Guerra B. Protein kinase CK2 subunits are positive regulators of AKT kinase. Int J Oncol. 2006;28:685–93.PubMed
39.
Channavajhala P, Seldin DC. Functional interaction of protein kinase CK2 and c-Myc in lymphomagenesis. Oncogene. 2002;21:5280–8.CrossRefPubMed
40.
Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Sonenshein GE. Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells. Cancer Res. 2002;62:6770–8.PubMed
41.
Landesman-Bollag E, Romieu-Mourez R, Song DH, Sonenshein GE, Cardiff RD, Seldin DC. Protein kinase CK2 in mammary gland tumorigenesis. Oncogene. 2001;20:3247–57.CrossRefPubMed
42.
O-charoenrat P, Rusch V, Talbot SG, Sarkaria I, Viale A, Socci N, et al. Casein kinase II alpha subunit and C1-inhibitor are independent predictors of outcome in patients with squamous cell carcinoma of the lung. Clin Cancer Res. 2004;10:5792–803.CrossRefPubMed
43.
Laramas M, Pasquier D, Filhol O, Ringeisen F, Descotes J-L, Cochet C. Nuclear localization of protein kinase CK2 catalytic subunit (CK2alpha) is associated with poor prognostic factors in human prostate cancer. Eur J Cancer. 2007;43:928–34.CrossRefPubMed
44.
Stalter G, Siemer S, Becht E, Ziegler M, Remberger K, Issinger OG. Asymmetric expression of protein kinase CK2 subunits in human kidney tumors. Biochem Biophys Res Commun. 1994;202:141–7.CrossRefPubMed
45.
Zhang X, Yang X, Yang C, Li P, Yuan W, Deng X, et al. Targeting protein kinase CK2 suppresses bladder cancer cell survival via the glucose metabolic pathway. Oncotarget. 2016;7:87361–72.PubMedPubMedCentral
46.
Zhou B, Ritt DA, Morrison DK, Der CJ, Cox AD. Protein kinase CK2alpha maintains extracellular signal-regulated kinase (ERK) activity in a CK2alpha kinase-independent manner to promote resistance to inhibitors of RAF and MEK but not ERK in BRAF mutant melanoma. J Biol Chem. 2016;291:17804–15.CrossRefPubMedPubMedCentral
47.
Mandato E, Manni S, Zaffino F, Semenzato G, Piazza F. Targeting CK2-driven non-oncogene addiction in B-cell tumors. Oncogene. 2016;35:6045–52.CrossRefPubMed
48.
Ruzzene M, Pinna LA. Addiction to protein kinase CK2: a common denominator of diverse cancer cells? Biochim Biophys Acta. 1804;2010:499–504.
49.
Broseus J, Chen G, Hergalant S, Ramstein G, Mounier N, Gueant J-L, et al. Relapsed diffuse large B-cell lymphoma present different genomic profiles between early and late relapses. Oncotarget. 2016;7:83987–4002.CrossRefPubMedPubMedCentral
50.
51.
Ponce DP, Yefi R, Cabello P, Maturana JL, Niechi I, Silva E, et al. CK2 functionally interacts with AKT/PKB to promote the beta-catenin-dependent expression of survivin and enhance cell survival. Mol Cell Biochem. 2011;356:127–32.CrossRefPubMed
52.
Park JH, Kim JJ, Bae Y-S. Involvement of PI3K-AKT-mTOR pathway in protein kinase CKII inhibition-mediated senescence in human colon cancer cells. Biochem Biophys Res Commun. 2013;433:420–5.CrossRefPubMed
53.
Ruzzene M, Bertacchini J, Toker A, Marmiroli S. Cross-talk between the CK2 and AKT signaling pathways in cancer. Adv Biol Regul. 2017;64:1–8.
54.
Quotti Tubi L, Canovas Nunes S, Brancalion A, Doriguzzi Breatta E, Manni S, Mandato E, et al. Protein kinase CK2 regulates AKT, NF-kappaB and STAT3 activation, stem cell viability and proliferation in acute myeloid leukemia. Leukemia. 2017;31:292–300.CrossRefPubMed
55.
Silva A, Jotta PY, Silveira AB, Ribeiro D, Brandalise SR, Yunes JA, et al. Regulation of PTEN by CK2 and Notch1 in primary T-cell acute lymphoblastic leukemia: rationale for combined use of CK2- and gamma-secretase inhibitors. Haematologica. 2010;95:674–8.CrossRefPubMed
56.
Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Traish AM, Mercurio F, Sonenshein GE. Roles of IKK kinases and protein kinase CK2 in activation of nuclear factor-kappaB in breast cancer. Cancer Res. 2001;61:3810–8.PubMed
57.
Ponce DP, Maturana JL, Cabello P, Yefi R, Niechi I, Silva E, et al. Phosphorylation of AKT/PKB by CK2 is necessary for the AKT-dependent up-regulation of beta-catenin transcriptional activity. J Cell Physiol. 2011;226:1953–9.CrossRefPubMed
58.
Zhang S, Yang Y-L, Wang Y, You B, Dai Y, Chan G, et al. CK2alpha, over-expressed in human malignant pleural mesothelioma, regulates the Hedgehog signaling pathway in mesothelioma cells. J Exp Clin Cancer Res. 2014;33:93.PubMedPubMedCentral
59.
Wang D, Westerheide SD, Hanson JL, Baldwin AS Jr. Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II. J Biol Chem. 2000;275:32592–7.CrossRefPubMed
60.
Seldin DC, Landesman-Bollag E, Farago M, Currier N, Lou D, Dominguez I. CK2 as a positive regulator of Wnt signalling and tumourigenesis. Mol Cell Biochem. 2005;274:63–7.CrossRefPubMed
61.
Gao Y, Wang HY. Casein kinase 2 is activated and essential for Wnt/beta-catenin signaling. J Biol Chem. 2006;281:18394–400.CrossRefPubMed
62.
Zhang S, Wang Y, Mao J-H, Hsieh D, Kim I-J, Hu L-M, et al. Inhibition of CK2alpha down-regulates Hedgehog/Gli signaling leading to a reduction of a stem-like side population in human lung cancer cells. PLoS One. 2012;7:e38996.CrossRefPubMedPubMedCentral
63.
Siddiqui-Jain A, Bliesath J, Macalino D, Omori M, Huser N, Streiner N, et al. CK2 inhibitor CX-4945 suppresses DNA repair response triggered by DNA-targeted anticancer drugs and augments efficacy: mechanistic rationale for drug combination therapy. Mol Cancer Ther. 2012;11:994–1005.CrossRefPubMed
64.
Olsen BB, Wang S-Y, Svenstrup TH, BPC C, Guerra B. Protein kinase CK2 localizes to sites of DNA double-strand break regulating the cellular response to DNA damage. BMC Mol Biol. 2012;13:7.CrossRefPubMedPubMedCentral
65.
Olsen BB, Svenstrup TH, Guerra B. Downregulation of protein kinase CK2 induces autophagic cell death through modulation of the mTOR and MAPK signaling pathways in human glioblastoma cells. Int J Oncol. 2012;41:1967–76.CrossRefPubMedPubMedCentral
66.
Buontempo F, Orsini E, Lonetti A, Cappellini A, Chiarini F, Evangelisti C, et al. Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: turning off the prosurvival ER chaperone BIP/Grp78 and turning on the pro-apoptotic NF-kappaB. Oncotarget. 2016;7:1323–40.CrossRefPubMed
67.
Turowec JP, Duncan JS, Gloor GB, Litchfield DW. Regulation of caspase pathways by protein kinase CK2: identification of proteins with overlapping CK2 and caspase consensus motifs. Mol Cell Biochem. 2011;356:159–67.CrossRefPubMed
68.
Turowec JP, Vilk G, Gabriel M, Litchfield DW. Characterizing the convergence of protein kinase CK2 and caspase-3 reveals isoform-specific phosphorylation of caspase-3 by CK2alpha': implications for pathological roles of CK2 in promoting cancer cell survival. Oncotarget. 2013;4:560–71.CrossRefPubMedPubMedCentral
69.
Parrish AB, Freel CD, Kornbluth S. Cellular mechanisms controlling caspase activation and function. Cold Spring Harb Perspect Biol. 2013;5:a008672.
70.
Kronke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND, et al. Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature. 2015;523:183–8.CrossRefPubMedPubMedCentral
71.
Piazza FA, Ruzzene M, Gurrieri C, Montini B, Bonanni L, Chioetto G, et al. Multiple myeloma cell survival relies on high activity of protein kinase CK2. Blood. 2006;108:1698–707.CrossRefPubMed
72.
Nishida MY, E. CK2 controls multiple protein kinases by phosphorylating a kinase-targeting molecular chaperone, Cdc37. Mol Cell Biol. 2004;24:4065–74.CrossRefPubMedPubMedCentral
73.
Miyata Y. Protein kinase CK2 in health and disease: CK2: the kinase controlling the Hsp90 chaperone machinery. Cell Mol Life Sci. 2009;66:1840–9.CrossRefPubMed
74.
Hessenauer A, Schneider CC, Gotz C, Montenarh M. CK2 inhibition induces apoptosis via the ER stress response. Cell Signal. 2011;23:145–51.CrossRefPubMed
75.
Muller P, Ruckova E, Halada P, Coates PJ, Hrstka R, Lane DP, et al. C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances. Oncogene. 2013;32:3101–10.CrossRefPubMed
76.
Fernandez-Saiz V, Targosz BS, Lemeer S, Eichner R, Langer C, Bullinger L, et al. SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma. Nat Cell Biol. 2013;15:72–81.CrossRefPubMed
77.
Costa F, Vescovini R, Bolzoni M, Marchica V, Storti P, Toscani D, et al. Lenalidomide increases human dendritic cell maturation in multiple myeloma patients targeting monocyte differentiation and modulating mesenchymal stromal cell inhibitory properties: Oncotarget; 2017. doi:10.​18632/​oncotarget.​18085.
78.
An X, Tiwari AK, Sun Y, Ding P-R, Ashby CR Jr, Chen Z-S. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. Leuk Res. 2010;34:1255–68.CrossRefPubMed
79.
Jerkeman M, Hallek M, Dreyling M, Thieblemont C, Kimby E, Staudt L. Targeting of B-cell receptor signalling in B-cell malignancies. J Intern Med. 2017. doi:10.​1111/​joim.​12600.
80.
81.
Pizzi M, Piazza F, Agostinelli C, Fuligni F, Benvenuti P, Mandato E, et al. Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth. Oncotarget. 2015;6:6544–52.CrossRefPubMedPubMedCentral
82.
Quotti Tubi L, Gurrieri C, Brancalion A, Bonaldi L, Bertorelle R, Manni S, et al. Inhibition of protein kinase CK2 with the clinical-grade small ATP-competitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity. J Hematol Oncol. 2013;6:78.CrossRefPubMedPubMedCentral
83.
Prins RC, Burke RT, Tyner JW, Druker BJ, Loriaux MM, Spurgeon SE. CX-4945, a selective inhibitor of casein kinase-2 (CK2), exhibits anti-tumor activity in hematologic malignancies including enhanced activity in chronic lymphocytic leukemia when combined with fludarabine and inhibitors of the B-cell receptor pathway. Leukemia. 2013;27:2094–6.CrossRefPubMed
84.
Martins LR, Perera Y, Lucio P, Silva MG, Perea SE, Barata JT. Targeting chronic lymphocytic leukemia using CIGB-300, a clinical-stage CK2-specific cell-permeable peptide inhibitor. Oncotarget. 2014;5:258–63.CrossRefPubMed
85.
Chon HJ, Bae KJ, Lee Y, Kim J. The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies. Front Pharmacol. 2015;6:70.CrossRefPubMedPubMedCentral
Metadata
Title
Role of protein kinases CK1α and CK2 in multiple myeloma: regulation of pivotal survival and stress-managing pathways
Authors
Sabrina Manni
Marilena Carrino
Francesco Piazza
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2017
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-017-0529-5

Other articles of this Issue 1/2017

Journal of Hematology & Oncology 1/2017 Go to the issue

Review

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

Review

New treatment options for metastatic renal cell carcinoma with prior anti-angiogenesis therapy

Research

Observational study of lenalidomide in patients with mantle cell lymphoma who relapsed/progressed after or were refractory/intolerant to ibrutinib (MCL-004)

Review

Recent development in clinical applications of PD-1 and PD-L1 antibodies for cancer immunotherapy

Research

Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression

Letter to the Editor

Spectrum of somatic mutations detected by targeted next-generation sequencing and their prognostic significance in adult patients with acute lymphoblastic leukemia
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits