title: The epichaperome is an integrated chaperome network that facilitates tumour survival.
abstract: Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically 'rewired' to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Rodina
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Tai
authors.initials: T
authors.lastname: Wang
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Pengrong
authors.initials: P
authors.lastname: Yan
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Erica DaGama
authors.initials: ED
authors.lastname: Gomes
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Mark P S
authors.initials: MP
authors.lastname: Dunphy
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Nagavarakishore
authors.initials: N
authors.lastname: Pillarsetty
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: John
authors.initials: J
authors.lastname: Koren
authors.affiliation: Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Gerecitano
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Taldone
authors.affiliation: Haematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Zong
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Eloisi
authors.initials: E
authors.lastname: Caldas-Lopes
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Alpaugh
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Corben
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Riolo
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Beattie
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Pressl
authors.affiliation: Department of Mathematics, Technical University of Cluj-Napoca, Cluj-Napoca 400114, Romania.
authors.forename: Radu I
authors.initials: RI
authors.lastname: Peter
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Trondl
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Hardik J
authors.initials: HJ
authors.lastname: Patel
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Shimizu
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bolaender
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Chenghua
authors.initials: C
authors.lastname: Yang
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Palak
authors.initials: P
authors.lastname: Panchal
authors.affiliation: Molecular, Cellular &Biomedical Sciences, University of New Hampshire, Durham, New Hampshire 03824, USA.
authors.forename: Mohammad F
authors.initials: MF
authors.lastname: Farooq
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kishinevsky
authors.affiliation: Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Shanu
authors.initials: S
authors.lastname: Modi
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Lin
authors.affiliation: Molecular, Cellular &Biomedical Sciences, University of New Hampshire, Durham, New Hampshire 03824, USA.
authors.forename: Feixia
authors.initials: F
authors.lastname: Chu
authors.affiliation: Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Patil
authors.affiliation: Microchemistry and Proteomics Core, Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Pat
authors.initials: P
authors.lastname: Zanzonico
authors.affiliation: Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Clifford
authors.initials: C
authors.lastname: Hudis
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
authors.affiliation: Haematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Roboz
authors.affiliation: Haematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Ethel
authors.initials: E
authors.lastname: Cesarman
authors.affiliation: Haematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.affiliation: Human Oncology and Pathogenesis Program, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Levine
authors.affiliation: Haematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: Haematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Guzman
authors.affiliation: Program in Chemical Biology, Sloan Kettering Institute, New York, New York 10065, USA.|Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D055808:Drug Discovery; D005260:Female; D016259:Genes, myc / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009928:Organ Specificity
chemical_list: D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D046912:Multiprotein Complexes