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Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | osteosarcoma | Research article

Interaction between the BAG1S isoform and HSP70 mediates the stability of anti-apoptotic proteins and the survival of osteosarcoma cells expressing oncogenic MYC

Authors: Victoria J. Gennaro, Helen Wedegaertner, Steven B. McMahon

Published in: BMC Cancer | Issue 1/2019

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Abstract

Background

The oncoprotein MYC has the dual capacity to drive cell cycle progression or induce apoptosis, depending on the cellular context. BAG1 was previously identified as a transcriptional target of MYC that functions as a critical determinant of this cell fate decision. The BAG1 protein is expressed as multiple isoforms, each having an array of distinct biochemical functions; however, the specific effector function of BAG1 that directs MYC-dependent cell survival has not been defined.

Methods

In our studies the human osteosarcoma line U2OS expressing a conditional MYC-ER allele was used to induce oncogenic levels of MYC. We interrogated MYC-driven survival processes by modifying BAG1 protein expression. The function of the separate BAG1 isoforms was investigated by depleting cells of endogenous BAG1 and reintroducing the distinct isoforms. Flow cytometry and immunoblot assays were performed to analyze the effect of specific BAG1 isoforms on MYC-dependent apoptosis. These experiments were repeated to determine the role of the HSP70 chaperone complex in BAG1 survival processes. Finally, a proteomic approach was used to identify a set of specific pro-survival proteins controlled by the HSP70/BAG1 complex.

Results

Loss of BAG1 resulted in robust MYC-induced apoptosis. Expression of the larger isoforms of BAG1, BAG1L and BAG1M, were insufficient to rescue survival in cells with oncogenic levels of MYC. Alternatively, reintroduction of BAG1S significantly reduced the level of apoptosis. Manipulation of the BAG1S interaction with HSP70 revealed that BAG1S provides its pro-survival function by serving as a cofactor for the HSP70 chaperone complex. Via a proteomic approach we identified and classified a set of pro-survival proteins controlled by this HSP70/BAG1 chaperone complex that contribute to the BAG1 anti-apoptotic phenotype.

Conclusions

The small isoform of BAG1, BAG1S, in cooperation with the HSP70 chaperone complex, selectively mediates cell survival in MYC overexpressing tumor cells. We identified a set of specific pro-survival clients controlled by the HSP70/BAG1S chaperone complex. These clients define new nodes that could be therapeutically targeted to disrupt the survival of tumor cells driven by MYC activation. With MYC overexpression occurring in most human cancers, this introduces new strategies for cancer treatment.
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Literature
1.
2.
Walz S, Lorenzin F, Morton J, Wiese KE, von Eyss B, Herold S, et al. Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature. 2014;511(7510):483–7.PubMedCrossRefPubMedCentral
3.
4.
Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and human neoplastic disease. Oncogene. 1999;18(19):3004–16.PubMedCrossRef
5.
Zhang X-Y, Pfeiffer HK, Mellert HS, Stanek TJ, Sussman RT, Kumari A, et al. Inhibition of the Single Downstream Target BAG1 Activates the Latent Apoptotic Potential of MYC. Mol Cell Biol. 2011;31(24):5037–45.
6.
Batistatou A, Kyzas PA, Goussia A, Arkoumani E, Voulgaris S, Polyzoidis K, et al. Estrogen receptor beta (ERbeta) protein expression correlates with BAG-1 and prognosis in brain glial tumours. J Neuro-Oncol. 2006;77(1):17–23.CrossRef
7.
Clemo NK, Collard TJ, Southern SL, Edwards KD, Moorghen M, Packham G, et al. BAG-1 is up-regulated in colorectal tumour progression and promotes colorectal tumour cell survival through increased NF-kappaB activity. Carcinogenesis. 2008;29(4):849–57.PubMedCrossRef
8.
Krajewska M, Turner BC, Shabaik A, Krajewski S, Reed JC. Expression of BAG-1 protein correlates with aggressive behavior of prostate cancers. Prostate. 2006;66(8):801–10.PubMedCrossRef
9.
Yang X, Chernenko G, Hao Y, Ding Z, Pater MM, Pater A, et al. Human BAG-1/RAP46 protein is generated as four isoforms by alternative translation initiation and overexpressed in cancer cells. Oncogene. 1998;17(8):981–9.PubMedCrossRef
10.
Takayama S, Kochel K, Irie S, Inazawa J, Abe T, Sato T, et al. Cloning of cDNAs encoding the human BAG1 protein and localization of the human BAG1 gene to chromosome 9p12. Genomics. 1996;35(3):494–8.PubMedCrossRef
11.
Takayama S, Krajewski S, Krajewska M, Kitada S, Zapata JM, Kochel K, et al. Expression and location of Hsp70/Hsc-binding anti-apoptotic protein BAG-1 and its variants in normal tissues and tumor cell lines. Cancer Res. 1998;58(14):3116–31.PubMed
12.
Luders J, Demand J, Papp O, Hohfeld J. Distinct isoforms of the cofactor BAG-1 differentially affect Hsc70 chaperone function. J Biol Chem. 2000;275(20):14817–23.PubMedCrossRef
13.
Kanelakis KC, Morishima Y, Dittmar KD, Galigniana MD, Takayama S, Reed JC, et al. Differential effects of the hsp70-binding protein BAG-1 on glucocorticoid receptor folding by the hsp90-based chaperone machinery. J Biol Chem. 1999;274(48):34134–40.PubMedCrossRef
14.
Cato AC, Mink S. BAG-1 family of cochaperones in the modulation of nuclear receptor action. J Steroid Biochem Mol Biol. 2001;78(5):379–88.PubMedCrossRef
15.
Niyaz Y, Frenz I, Petersen G, Gehring U. Transcriptional stimulation by the DNA binding protein Hap46/BAG-1M involves hsp70/hsc70 molecular chaperones. Nucleic Acids Res. 2003;31(8):2209–16.PubMedPubMedCentralCrossRef
16.
Niyaz Y, Zeiner M, Gehring U. Transcriptional activation by the human Hsp70-associating protein Hap50. J Cell Sci. 2001;114(Pt 10):1839–45.PubMed
17.
Zeiner M, Niyaz Y, Gehring U. The hsp70-associating protein Hap46 binds to DNA and stimulates transcription. Proc Natl Acad Sci U S A. 1999;96(18):10194–9.PubMedPubMedCentralCrossRef
18.
Gehring U. Biological activities of HAP46/BAG-1. The HAP46/BAG-1 protein: regulator of HSP70 chaperones, DNA-binding protein and stimulator of transcription. EMBO Rep. 2004;5(2):148–53.PubMedPubMedCentralCrossRef
19.
Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteomics. 2014;13(9):2513–26.PubMedPubMedCentralCrossRef
20.
Littlewood TD, Hancock DC, Danielian PS, Parker MG, Evan GI. A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins. Nucleic Acids Res. 1995;23(10):1686–90.PubMedPubMedCentralCrossRef
21.
Eilers M, Picard D, Yamamoto KR, Bishop JM. Chimaeras of Myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells. Nature. 1989;340:66.PubMedCrossRef
22.
Popov N, Wanzel M, Madiredjo M, Zhang D, Beijersbergen R, Bernards R, et al. The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol. 2007;9(7):765–74.PubMedCrossRef
23.
Packham G, Brimmell M, Cleveland JL. Mammalian cells express two differently localized bag-1 isoforms generated by alternative translation initiation. Biochem J. 1997;328(Pt 3):807–13.PubMedPubMedCentralCrossRef
24.
Takayama S, Reed JC. Molecular chaperone targeting and regulation by BAG family proteins. Nat Cell Biol. 2001;3(10):E237–41.PubMedCrossRef
25.
Brimmell M, Burns JS, Munson P, McDonald L, O'Hare MJ, Lakhani SR, et al. High level expression of differentially localized BAG-1 isoforms in some oestrogen receptor-positive human breast cancers. Br J Cancer. 1999;81(6):1042–51.PubMedPubMedCentralCrossRef
26.
27.
Daugaard M, Rohde M, Jaattela M. The heat shock protein 70 family: highly homologous proteins with overlapping and distinct functions. FEBS Lett. 2007;581(19):3702–10.PubMedCrossRef
28.
Grad I, Picard D. The glucocorticoid responses are shaped by molecular chaperones. Mol Cell Endocrinol. 2007;275(1–2):2–12.PubMedCrossRef
29.
30.
Cheetham ME, Caplan AJ. Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function. Cell Stress Chaperones. 1998;3(1):28–36.PubMedPubMedCentralCrossRef
31.
Frydman J, Hohfeld J. Chaperones get in touch: the hip-hop connection. Trends Biochem Sci. 1997;22(3):87–92.PubMedCrossRef
32.
33.
Brive L, Takayama S, Briknarova K, Homma S, Ishida SK, Reed JC, et al. The carboxyl-terminal lobe of Hsc70 ATPase domain is sufficient for binding to BAG1. Biochem Biophys Res Commun. 2001;289(5):1099–105.PubMedCrossRef
34.
Townsend PA, Cutress RI, Sharp A, Brimmell M, Packham G. BAG-1: a multifunctional regulator of cell growth and survival. Biochim Biophys Acta. 2003;1603(2):83–98.PubMed
35.
Gebauer M, Zeiner M, Gehring U. Proteins interacting with the molecular chaperone hsp70/hsc70: physical associations and effects on refolding activity. FEBS Lett. 1997;417(1):109–13.PubMedCrossRef
36.
Zeiner M, Gebauer M, Gehring U. Mammalian protein RAP46: an interaction partner and modulator of 70 kDa heat shock proteins. EMBO J. 1997;16(18):5483–90.PubMedPubMedCentralCrossRef
37.
Sondermann H, Scheufler C, Schneider C, Hohfeld J, Hartl FU, Moarefi I. Structure of a bag/Hsc70 complex: convergent functional evolution of Hsp70 nucleotide exchange factors. Science. 2001;291(5508):1553–7.PubMedCrossRef
38.
Gebauer M, Melki R, Gehring U. The chaperone cofactor hop/p60 interacts with the cytosolic chaperonin-containing TCP-1 and affects its nucleotide exchange and protein folding activities. J Biol Chem. 1998;273(45):29475–80.PubMedCrossRef
39.
Goldberg AL. Protein degradation and protection against misfolded or damaged proteins. Nature. 2003;426(6968):895–9.PubMedCrossRef
40.
Kleizen B, Braakman I. Protein folding and quality control in the endoplasmic reticulum. Curr Opin Cell Biol. 2004;16(4):343–9.PubMedCrossRef
41.
Lee S, Lee DW, Lee Y, Mayer U, Stierhof YD, Lee S, et al. Heat shock protein cognate 70-4 and an E3 ubiquitin ligase, CHIP, mediate plastid-destined precursor degradation through the ubiquitin-26S proteasome system in Arabidopsis. Plant Cell. 2009;21(12):3984–4001.PubMedPubMedCentralCrossRef
42.
Sroka K, Voigt A, Deeg S, Reed JC, Schulz JB, Bahr M, et al. BAG1 modulates huntingtin toxicity, aggregation, degradation, and subcellular distribution. J Neurochem. 2009;111(3):801–7.PubMedCrossRef
43.
Song J, Takeda M, Morimoto RI. Bag1-Hsp70 mediates a physiological stress signalling pathway that regulates Raf-1/ERK and cell growth. Nat Cell Biol. 2001;3(3):276–82.PubMedCrossRef
44.
Alberti S, Esser C, Hohfeld J. BAG-1--a nucleotide exchange factor of Hsc70 with multiple cellular functions. Cell Stress Chaperones. 2003;8(3):225–31.PubMedPubMedCentralCrossRef
45.
Luders J, Demand J, Hohfeld J. The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome. J Biol Chem. 2000;275(7):4613–7.PubMedCrossRef
46.
Alberti S, Demand J, Esser C, Emmerich N, Schild H, Hohfeld J. Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome. J Biol Chem. 2002;277(48):45920–7.PubMedCrossRef
47.
Cesa LC, Shao H, Srinivasan SR, Tse E, Jain C, Zuiderweg ERP, et al. X-linked inhibitor of apoptosis protein (XIAP) is a client of heat shock protein 70 (Hsp70) and a biomarker of its inhibition. J Biol Chem. 2018;293(7):2370–80.PubMedCrossRef
48.
Almajan ER, Richter R, Paeger L, Martinelli P, Barth E, Decker T, et al. AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. J Clin Invest. 2012;122(11):4048–58.PubMedPubMedCentralCrossRef
49.
Almontashiri NA, Chen HH, Mailloux RJ, Tatsuta T, Teng AC, Mahmoud AB, et al. SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes. Cell Rep. 2014;7(3):834–47.PubMedCrossRef
50.
Ikeda S, Kitadate A, Abe F, Saitoh H, Michishita Y, Hatano Y, et al. Hypoxia-inducible microRNA-210 regulates the DIMT1-IRF4 oncogenic axis in multiple myeloma. Cancer Sci. 2017;108(4):641–52.PubMedPubMedCentralCrossRef
51.
Spruijt CG, Luijsterburg MS, Menafra R, Lindeboom RG, Jansen PW, Edupuganti RR, et al. ZMYND8 co-localizes with NuRD on target genes and regulates poly (ADP-ribose)-dependent recruitment of GATAD2A/NuRD to sites of DNA damage. Cell Rep. 2016;17(3):783–98.PubMedCrossRef
52.
Garg M, Braunstein G, Koeffler HP. LAMC2 as a therapeutic target for cancers. Expert Opin Ther Targets. 2014;18(9):979–82.PubMedCrossRef
53.
Zhu M, Settele F, Kotak S, Sanchez-Pulido L, Ehret L, Ponting CP, et al. MISP is a novel Plk1 substrate required for proper spindle orientation and mitotic progression. J Cell Biol. 2013;200(6):773–87.PubMedPubMedCentralCrossRef
54.
Zhou Z, Wang L, Ge F, Gong P, Wang H, Wang F, et al. Pold3 is required for genomic stability and telomere integrity in embryonic stem cells and meiosis. Nucleic Acids Res. 2018;46(7):3468–86.PubMedPubMedCentralCrossRef
55.
Noack Watt KE, Achilleos A, Neben CL, Merrill AE, Trainor PA. The roles of RNA polymerase I and III subunits Polr1c and Polr1d in craniofacial development and in zebrafish models of Treacher Collins syndrome. PLoS Genet. 2016;12(7):e1006187.PubMedPubMedCentralCrossRef
56.
Ruisu K, Kask K, Meier R, Saare M, Raid R, Veraksits A, et al. Ablation of RIC8A function in mouse neurons leads to a severe neuromuscular phenotype and postnatal death. PLoS One. 2013;8(8):e74031.PubMedPubMedCentralCrossRef
57.
Bhutia YD, Babu E, Ramachandran S, Ganapathy V. Amino acid transporters in cancer and their relevance to “glutamine addiction”: novel targets for the design of a new class of anticancer drugs. Cancer Res. 2015;75(9):1782–8.PubMedCrossRef
58.
Liu P, Ge M, Hu J, Li X, Che L, Sun K, et al. A functional mammalian target of rapamycin complex 1 signaling is indispensable for c-Myc-driven hepatocarcinogenesis. Hepatology. 2017;66(1):167–81.PubMedCrossRef
59.
Ballarino M, Jobert L, Dembele D, de la Grange P, Auboeuf D, Tora L. TAF15 is important for cellular proliferation and regulates the expression of a subset of cell cycle genes through miRNAs. Oncogene. 2013;32(39):4646–55.PubMedCrossRef
60.
Beaulieu CL, Huang L, Innes AM, Akimenko MA, Puffenberger EG, Schwartz C, et al. Intellectual disability associated with a homozygous missense mutation in THOC6. Orphanet J Rare Dis. 2013;8:62.PubMedPubMedCentralCrossRef
61.
Yamashita A, Taniwaki T, Kaikoi Y, Yamazaki T. Protective role of the endoplasmic reticulum protein mitsugumin23 against ultraviolet C-induced cell death. FEBS Lett. 2013;587(9):1299–303.PubMedCrossRef
62.
Hu L, Wang J, Liu Y, Zhang Y, Zhang L, Kong R, et al. A small ribosomal subunit (SSU) processome component, the human U3 protein 14A (hUTP14A) binds p53 and promotes p53 degradation. J Biol Chem. 2011;286(4):3119–28.PubMedCrossRef
63.
Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483(7391):603–7.PubMedPubMedCentralCrossRef
64.
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
65.
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):pl1.PubMedPubMedCentralCrossRef
66.
Faumont N, Durand-Panteix S, Schlee M, Gromminger S, Schuhmacher M, Holzel M, et al. C-Myc and Rel/NF-kappaB are the two master transcriptional systems activated in the latency III program of Epstein-Barr virus-immortalized B cells. J Virol. 2009;83(10):5014–27.PubMedPubMedCentralCrossRef
67.
Campbell KJ, White RJ. MYC regulation of cell growth through control of transcription by RNA polymerases I and III. Cold Spring Harb Perspect Med. 2014;4(5):a018408.
68.
Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. C-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458(7239):762–5.PubMedPubMedCentralCrossRef
69.
Sakuma K, Aoki M, Kannagi R. Transcription factors c-Myc and CDX2 mediate E-selectin ligand expression in colon cancer cells undergoing EGF/bFGF-induced epithelial-mesenchymal transition. Proc Natl Acad Sci U S A. 2012;109(20):7776–81.PubMedPubMedCentralCrossRef
70.
Kessler JD, Kahle KT, Sun T, Meerbrey KL, Schlabach MR, Schmitt EM, et al. A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science. 2012;335(6066):348–53.PubMedCrossRef
71.
Liu CI, Jeng WY, Chang WJ, Ko TP, Wang AH. Binding modes of zaragozic acid a to human squalene synthase and staphylococcal dehydrosqualene synthase. J Biol Chem. 2012;287(22):18750–7.PubMedPubMedCentralCrossRef
72.
Spearman MA, Ballon BC, Gerrard JM, Greenberg AH, Wright JA. The inhibition of platelet aggregation of metastatic H-ras-transformed 10T1/2 fibroblasts with castanospermine, an N-linked glycoprotein processing inhibitor. Cancer Lett. 1991;60(3):185–91.PubMedCrossRef
73.
Colis L, Peltonen K, Sirajuddin P, Liu H, Sanders S, Ernst G, et al. DNA intercalator BMH-21 inhibits RNA polymerase I independent of DNA damage response. Oncotarget. 2014;5(12):4361–9.PubMedPubMedCentralCrossRef
74.
Drygin D, Lin A, Bliesath J, Ho CB, O'Brien SE, Proffitt C, et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 2011;71(4):1418–30.PubMedCrossRef
75.
76.
Knee DA, Froesch BA, Nuber U, Takayama S, Reed JC. Structure-function analysis of Bag1 proteins. Effects on androgen receptor transcriptional activity. J Biol Chem. 2001;276(16):12718–24.PubMedCrossRef
77.
Schneikert J, Hubner S, Martin E, Cato AC. A nuclear action of the eukaryotic cochaperone RAP46 in downregulation of glucocorticoid receptor activity. J Cell Biol. 1999;146(5):929–40.PubMedPubMedCentralCrossRef
78.
Froesch BA, Takayama S, Reed JC. BAG-1L protein enhances androgen receptor function. J Biol Chem. 1998;273(19):11660–6.PubMedCrossRef
79.
Witcher M, Yang X, Pater A, Tang SC. BAG-1 p50 isoform interacts with the vitamin D receptor and its cellular overexpression inhibits the vitamin D pathway. Exp Cell Res. 2001;265(1):167–73.PubMedCrossRef
80.
Guzey M, Takayama S, Reed JC. BAG1L enhances trans-activation function of the vitamin D receptor. J Biol Chem. 2000;275(52):40749–56.PubMedCrossRef
81.
Da Costa CR, Villadiego J, Sancho R, Fontana X, Packham G, Nateri AS, et al. Bag1-L is a phosphorylation-dependent coactivator of c-Jun during neuronal apoptosis. Mol Cell Biol. 2010;30(15):3842–52.PubMedPubMedCentralCrossRef
82.
Cutress RI, Townsend PA, Sharp A, Maison A, Wood L, Lee R, et al. The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription. Oncogene. 2003;22(32):4973–82.PubMedCrossRef
Metadata
Title
Interaction between the BAG1S isoform and HSP70 mediates the stability of anti-apoptotic proteins and the survival of osteosarcoma cells expressing oncogenic MYC
Authors
Victoria J. Gennaro
Helen Wedegaertner
Steven B. McMahon
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-5454-2

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