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
BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

DKK1 is a potential novel mediator of cisplatin-refractoriness in non-small cell lung cancer cell lines

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

Platinum compounds are the mainstay of chemotherapy for lung cancer. Unfortunately treatment failure remains a critical issue since about 60 % of all non-small cell lung cancer (NSCLC) patients display intrinsic platinum resistance.

Methods

We analyzed global gene expression profiles of NSCLC clones surviving a pulse treatment with cisplatin and mapped deregulated signaling networks in silico by Ingenuity Pathway Analysis (IPA). Further validation was done using siRNA.

Results

The pooled cisplatin-surviving NSCLC clones from each of the biological replicates demonstrated heterogeneous gene expression patterns both in terms of the number and the identity of the altered genes. Genes involved in Wnt signaling pathway (Dickkopf-1, DKK1), DNA repair machinery (XRCC2) and cell-cell/cell-matrix interaction (FMN1, LGALS9) were among the top deregulated genes by microarray in these replicates and were validated by q-RT-PCR. We focused on DKK1 which previously was reported to be overexpressed in NSCLC patients. IPA network analysis revealed coordinate up-regulation of several DKK1 transcriptional regulators (TCF4, EZH2, DNAJB6 and HDAC2) in cisplatin-surviving clones from that biological replicate. Knockdown of DKK1 by siRNA sensitized for cisplatin in two different NSCLC cell lines and in ovarian A2780 cells, but not in the A2780 cis subline made resistant to cisplatin by chronic exposure, suggesting a role of DKK1 in intrinsic but not acquired platinum refractoriness.

Conclusions

We identified DKK1 as a possible marker of a cisplatin-refractory phenotype and as a potential novel therapeutic target to improve platinum response of NSCLC cells.
Appendix
Available only for authorised users
Literature
1.
Cagle PT, Allen TC. Lung cancer genotype-based therapy and predictive biomarkers: present and future. Arch Pathol Lab Med. 2012;136(12):1482–91.CrossRefPubMed
2.
Yeung K, Carlson JJ. Clinical and economic review of erlotinib in non-small-cell lung cancer. Expert Rev Pharmacoecon Outcomes Res. 2012;12(4):411–23.CrossRefPubMed
3.
Shen DW, Pouliot LM, Hall MD, Gottesman MM. Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol Rev. 2012;64(3):706–21.CrossRefPubMedPubMedCentral
4.
Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31(15):1869–83.CrossRefPubMed
5.
Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006;355(10):983–91.CrossRefPubMed
6.
Rosell R, Danenberg KD, Alberola V, Bepler G, Sanchez JJ, Camps C, et al. Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res. 2004;10(4):1318–25.CrossRefPubMed
7.
Mohammed Ael S, Eguchi H, Wada S, Koyama N, Shimizu M, Otani K, et al. TMEM158 and FBLP1 as novel marker genes of cisplatin sensitivity in non-small cell lung cancer cells. Exp Lung Res. 2012;38(9-10):463–74.CrossRefPubMed
8.
Oiso S, Takayama Y, Nakazaki R, Matsunaga N, Motooka C, Yamamura A, Ikeda R, Nakamura K, Takeda Y, Kariyazono H: Factors involved in the cisplatin resistance of KCP4 human epidermoid carcinoma cells. Oncol Rep. 2014;31(2):719-26.
9.
Bergh J, Nilsson K, Ekman R, Giovanella B. Establishment and characterization of cell lines from human small cell and large cell carcinomas of the lung. Acta Pathol Microbiol Immunol Scand A. 1985;93(3):133–47.PubMed
10.
Rio DC, Ares Jr M, Hannon GJ, Nilsen TW. Purification of RNA using TRIzol (TRI reagent). Cold Spring Harb Protoc. 2010;2010:6. pdb prot5439.
11.
Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30(1):207–10.CrossRefPubMedPubMedCentral
12.
Salim H, Arvanitis A, de Petris L, Kanter L, Haag P, Zovko A, et al. miRNA-214 is related to invasiveness of human non-small cell lung cancer and directly regulates alpha protein kinase 2 expression. Genes Chromosomes Cancer. 2013;52(10):895–911.CrossRefPubMed
13.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8.CrossRefPubMed
14.
Lundholm L, Haag P, Zong D, Juntti T, Mork B, Lewensohn R, et al. Resistance to DNA-damaging treatment in non-small cell lung cancer tumor-initiating cells involves reduced DNA-PK/ATM activation and diminished cell cycle arrest. Cell Death Dis. 2013;4:e478.CrossRefPubMedPubMedCentral
15.
Goodisman J, Souid AK. Constancy in integrated cisplatin plasma concentrations among pediatric patients. J Clin Pharmacol. 2006;46(4):443–8.CrossRefPubMed
16.
Dettenhofer M, Zhou F, Leder P. Formin 1-isoform IV deficient cells exhibit defects in cell spreading and focal adhesion formation. PLoS One. 2008;3(6):e2497.CrossRefPubMedPubMedCentral
17.
18.
Sato N, Yamabuki T, Takano A, Koinuma J, Aragaki M, Masuda K, et al. Wnt inhibitor Dickkopf-1 as a target for passive cancer immunotherapy. Cancer Res. 2010;70(13):5326–36.CrossRefPubMed
19.
Yonetani Y, Hochegger H, Sonoda E, Shinya S, Yoshikawa H, Takeda S, et al. Differential and collaborative actions of Rad51 paralog proteins in cellular response to DNA damage. Nucleic Acids Res. 2005;33(14):4544–52.CrossRefPubMedPubMedCentral
20.
Yamabuki T, Takano A, Hayama S, Ishikawa N, Kato T, Miyamoto M, et al. Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas. Cancer Res. 2007;67(6):2517–25.CrossRefPubMed
21.
Li S, Qin X, Guo X, Cui A, He Y, Wei S, et al. Dickkopf-1 is oncogenic and involved in invasive growth in non small cell lung cancer. PLoS One. 2013;8(12):e84944.CrossRefPubMedPubMedCentral
22.
Pinto D, Gregorieff A, Begthel H, Clevers H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 2003;17(14):1709–13.CrossRefPubMedPubMedCentral
23.
Zhang DY, Wang HJ, Tan YZ. Wnt/b-Catenin Signaling Induces the Aging of Mesenchymal Stem Cells through the DNA Damage Response and the p53/p21 Pathway. PLoS One. 2011;6(6):e21397.CrossRefPubMedPubMedCentral
24.
Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, et al. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. J Neurosci. 2004;24(26):6021–7.CrossRefPubMed
25.
Salcedo-Tello P, Hernandez-Ortega K, Arias C. Susceptibility to GSK3beta-induced tau phosphorylation differs between the young and aged hippocampus after Wnt signaling inhibition. J Alzheimers Dis. 2014;39(4):775–85.PubMed
26.
Zhang QG, Wang R, Khan M, Mahesh V, Brann DW. Role of Dickkopf-1, an antagonist of the Wnt/beta-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation. J Neurosci. 2008;28(34):8430–41.CrossRefPubMedPubMedCentral
27.
Gortazar AR, Martin-Millan M, Bravo B, Plotkin LI, Bellido T. Crosstalk between caveolin-1/extracellular signal-regulated kinase (ERK) and beta-catenin survival pathways in osteocyte mechanotransduction. J Biol Chem. 2013;288(12):8168–75.CrossRefPubMedPubMedCentral
28.
Fortress AM, Schram SL, Tuscher JJ, Frick KM. Canonical Wnt signaling is necessary for object recognition memory consolidation. J Neurosci. 2013;33(31):12619–26.CrossRefPubMed
29.
Guo AJ, Choi RC, Cheung AW, Chen VP, Xu SL, Dong TT, et al. Baicalin, a flavone, induces the differentiation of cultured osteoblasts: an action via the Wnt/beta-catenin signaling pathway. J Biol Chem. 2011;286(32):27882–93.CrossRefPubMedPubMedCentral
30.
Kuhnert F, Davis CR, Wang HT, Chu P, Lee M, Yuan J, et al. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc Natl Acad Sci U S A. 2004;101(1):266–71.CrossRefPubMed
31.
Gillespie JR, Bush JR, Bell GI, Aubrey LA, Dupuis H, Ferron M, et al. GSK-3beta function in bone regulates skeletal development, whole-body metabolism, and male life span. Endocrinology. 2013;154(10):3702–18.CrossRefPubMed
32.
Roberts S, Delury C, Marsh E. The PDZ protein discs-large (DLG): the 'Jekyll and Hyde' of the epithelial polarity proteins. FEBS J. 2012;279(19):3549–58.CrossRefPubMed
33.
Sirzen F, Zhivotovsky B, Nilsson A, Bergh J, Lewensohn R. Spontaneous and radiation-induced apoptosis in lung carcinoma cells with different intrinsic radiosensitivities. Anticancer Res. 1998;18(2A):695–9.PubMed
34.
Altomare DA, Wang HQ, Skele KL, De Rienzo A, Klein-Szanto AJ, Godwin AK, et al. AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene. 2004;23(34):5853–7.CrossRefPubMed
35.
Yang X, Fraser M, Moll UM, Basak A, Tsang BK. Akt-mediated cisplatin resistance in ovarian cancer: modulation of p53 action on caspase-dependent mitochondrial death pathway. Cancer Res. 2006;66(6):3126–36.CrossRefPubMed
36.
Zhang J, Zhang LL, Shen L, Xu XM, Yu HG. Regulation of AKT gene expression by cisplatin. Oncol Lett. 2013;5(3):756–60.PubMedPubMedCentral
37.
Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the Bcl-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014;15(1):49–63.CrossRefPubMed
38.
Fulda S. Modulation of mitochondrial apoptosis by PI3K inhibitors. Mitochondrion. 2013;13(3):195–8.CrossRefPubMed
39.
Behrens BC, Hamilton TC, Masuda H, Grotzinger KR, Whang-Peng J, Louie KG, et al. Characterization of a cis-diamminedichloroplatinum(II)-resistant human ovarian cancer cell line and its use in evaluation of platinum analogues. Cancer Res. 1987;47(2):414–8.PubMed
40.
Chang A. Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer. 2011;71(1):3–10.CrossRefPubMed
41.
Galluzzi L, Morselli E, Vitale I, Kepp O, Senovilla L, Criollo A, et al. miR-181a and miR-630 regulate cisplatin-induced cancer cell death. Cancer Res. 2010;70(5):1793–803.CrossRefPubMed
42.
Gosepath EM, Eckstein N, Hamacher A, Servan K, von Jonquieres G, Lage H, et al. Acquired cisplatin resistance in the head-neck cancer cell line Cal27 is associated with decreased DKK1 expression and can partially be reversed by overexpression of DKK1. Int J Cancer. 2008;123(9):2013–9.CrossRefPubMed
43.
Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486(7404):532–6.PubMedPubMedCentral
44.
Diaz Jr LA, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486(7404):537–40.PubMedPubMedCentral
45.
Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008;15(3):504–14.CrossRefPubMed
46.
Imamdi R, de Graauw M, van de Water B. Protein kinase C mediates cisplatin-induced loss of adherens junctions followed by apoptosis of renal proximal tubular epithelial cells. J Pharmacol Exp Ther. 2004;311(3):892–903.CrossRefPubMed
47.
Tsaryk R, Fabian K, Thacker J, Kaina B. Xrcc2 deficiency sensitizes cells to apoptosis by MNNG and the alkylating anticancer drugs temozolomide, fotemustine and mafosfamide. Cancer Lett. 2006;239(2):305–13.CrossRefPubMed
48.
Chung LY, Tang SJ, Sun GH, Chou TY, Yeh TS, Yu SL, et al. Galectin-1 promotes lung cancer progression and chemoresistance by upregulating p38 MAPK, ERK, and cyclooxygenase-2. Clin Cancer Res. 2012;18(15):4037–47.CrossRefPubMed
49.
Kobayashi T, Shimura T, Yajima T, Kubo N, Araki K, Wada W, et al. Transient silencing of galectin-3 expression promotes both in vitro and in vivo drug-induced apoptosis of human pancreatic carcinoma cells. Clin Exp Metastasis. 2011;28(4):367–76.CrossRefPubMed
50.
Qiao L, Xu ZL, Zhao TJ, Ye LH, Zhang XD. Dkk-1 secreted by mesenchymal stem cells inhibits growth of breast cancer cells via depression of Wnt signalling. Cancer Lett. 2008;269(1):67–77.CrossRefPubMed
51.
Hirata H, Hinoda Y, Nakajima K, Kawamoto K, Kikuno N, Ueno K, et al. Wnt antagonist DKK1 acts as a tumor suppressor gene that induces apoptosis and inhibits proliferation in human renal cell carcinoma. Int J Cancer. 2011;128(8):1793–803.CrossRefPubMed
52.
Liu S, Howell P, Ren S, Fodstad O, Zhang G, Samant R, et al. Expression and functional analysis of the WAP four disulfide core domain 1 gene in human melanoma. Clin Exp Metastasis. 2009;26(7):739–49.CrossRefPubMed
53.
Peng S, Miao C, Li J, Fan X, Cao Y, Duan E. Dickkopf-1 induced apoptosis in human placental choriocarcinoma is independent of canonical Wnt signaling. Biochem Biophys Res Commun. 2006;350(3):641–7.CrossRefPubMed
54.
Shou J, Ali-Osman F, Multani AS, Pathak S, Fedi P, Srivenugopal KS. Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA. Oncogene. 2002;21(6):878–89.CrossRefPubMed
55.
Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349(26):2483–94.CrossRefPubMed
56.
Wirths O, Waha A, Weggen S, Schirmacher P, Kuhne T, Goodyer CG, et al. Overexpression of human Dickkopf-1, an antagonist of wingless/WNT signaling, in human hepatoblastomas and Wilms' tumors. Lab Invest. 2003;83(3):429–34.CrossRefPubMed
57.
Forget MA, Turcotte S, Beauseigle D, Godin-Ethier J, Pelletier S, Martin J, et al. The Wnt pathway regulator DKK1 is preferentially expressed in hormone-resistant breast tumours and in some common cancer types. Br J Cancer. 2007;96(4):646–53.CrossRefPubMedPubMedCentral
58.
Na Y, Lee SM, Kim DS, Park JY. Promoter methylation of Wnt antagonist DKK1 gene and prognostic value in Korean patients with non-small cell lung cancers. Cancer Biomark. 2012;12(2):73–9.PubMed
59.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.CrossRefPubMed
60.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):l1.CrossRef
61.
Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519–25.CrossRef
62.
Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543–50.CrossRef
63.
Gonzalez-Sancho JM, Aguilera O, Garcia JM, Pendas-Franco N, Pena C, Cal S, et al. The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene. 2005;24(6):1098–103.CrossRefPubMed
64.
Mitra A, Menezes ME, Shevde LA, Samant RS. DNAJB6 induces degradation of beta-catenin and causes partial reversal of mesenchymal phenotype. J Biol Chem. 2010;285(32):24686–94.CrossRefPubMedPubMedCentral
65.
Cheng AS, Lau SS, Chen Y, Kondo Y, Li MS, Feng H, et al. EZH2-mediated concordant repression of Wnt antagonists promotes beta-catenin-dependent hepatocarcinogenesis. Cancer Res. 2011;71(11):4028–39.CrossRefPubMed
66.
Hussain M, Rao M, Humphries AE, Hong JA, Liu F, Yang M, et al. Tobacco smoke induces polycomb-mediated repression of Dickkopf-1 in lung cancer cells. Cancer Res. 2009;69(8):3570–8.CrossRefPubMed
67.
Harms KL, Chen X. Histone deacetylase 2 modulates p53 transcriptional activities through regulation of p53-DNA binding activity. Cancer Res. 2007;67(7):3145–52.CrossRefPubMed
68.
Romanov VS, Pospelov VA, Pospelova TV. Cyclin-dependent kinase inhibitor p21(Waf1): contemporary view on its role in senescence and oncogenesis. Biochemistry (Mosc). 2012;77(6):575–84.CrossRef
69.
Wang H, Zhu LJ, Yang YC, Wang ZX, Wang R: MiR-224 promotes the chemoresistance of human lung adenocarcinoma cells to cisplatin via regulating G/S transition and apoptosis by targeting p21. Br J Cancer. 2014;111(2):339-54.
70.
Qu K, Lin T, Wei J, Meng F, Wang Z, Huang Z, et al. Cisplatin induces cell cycle arrest and senescence via upregulating P53 and P21 expression in HepG2 cells. Nan Fang Yi Ke Da Xue Xue Bao. 2013;33(9):1253–9.PubMed
71.
Cai G, Wang J, Xin X, Ke Z, Luo J. Phosphorylation of glycogen synthase kinase-3 beta at serine 9 confers cisplatin resistance in ovarian cancer cells. Int J Oncol. 2007;31(3):657–62.PubMed
72.
Gao Y, Liu Z, Zhang X, He J, Pan Y, Hao F, et al. Inhibition of cytoplasmic GSK-3beta increases cisplatin resistance through activation of Wnt/beta-catenin signaling in A549/DDP cells. Cancer Lett. 2013;336(1):231–9.CrossRefPubMed
73.
Erovic BM, Pelzmann M, Grasl M, Pammer J, Kornek G, Brannath W, et al. Mcl-1, vascular endothelial growth factor-R2, and 14-3-3sigma expression might predict primary response against radiotherapy and chemotherapy in patients with locally advanced squamous cell carcinomas of the head and neck. Clin Cancer Res. 2005;11(24 Pt 1):8632–6.CrossRefPubMed
74.
Han JY, Hong EK, Choi BG, Park JN, Kim KW, Kang JH, et al. Death receptor 5 and Bcl-2 protein expression as predictors of tumor response to gemcitabine and cisplatin in patients with advanced non-small-cell lung cancer. Med Oncol. 2003;20(4):355–62.CrossRefPubMed
75.
Michaud WA, Nichols AC, Mroz EA, Faquin WC, Clark JR, Begum S, et al. Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma. Clin Cancer Res. 2009;15(5):1645–54.CrossRefPubMedPubMedCentral
76.
Williams J, Lucas PC, Griffith KA, Choi M, Fogoros S, Hu YY, et al. Expression of Bcl-xL in ovarian carcinoma is associated with chemoresistance and recurrent disease. Gynecol Oncol. 2005;96(2):287–95.CrossRefPubMed
77.
Jain HV, Meyer-Hermann M. The molecular basis of synergism between carboplatin and ABT-737 therapy targeting ovarian carcinomas. Cancer Res. 2011;71(3):705–15.CrossRefPubMed
78.
Yu B, Yang X, Xu Y, Yao G, Shu H, Lin B, et al. Elevated expression of DKK1 is associated with cytoplasmic/nuclear beta-catenin accumulation and poor prognosis in hepatocellular carcinomas. J Hepatol. 2009;50(5):948–57.CrossRefPubMed
Metadata
Title
DKK1 is a potential novel mediator of cisplatin-refractoriness in non-small cell lung cancer cell lines
Publication date
01-12-2015
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1635-9

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Research article

Association between shift work and the risk of death from biliary tract cancer in Japanese men

Research article

IL6 secreted by Ewing sarcoma tumor microenvironment confers anti-apoptotic and cell-disseminating paracrine responses in Ewing sarcoma cells

Retraction Note

Retraction Note: STMN-1 is a potential marker of lymph node metastasis in distal esophageal adenocarcinomas and silencing its expression can reverse malignant phenotype of tumor cells

Research article

International trends in primary liver cancer incidence from 1973 to 2007

Research article

Representativeness of breast cancer cases in an integrated health care delivery system

Research article

Chromosomal instability as a prognostic marker in cervical cancer
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