Chaperome heterogeneity and its implications for cancer study and treatment

Abstract

The chaperome is the collection of proteins in the cell that carry out molecular chaperoning functions. Changes in the interaction strength between chaperome proteins lead to an assembly that is functionally and structurally distinct from each constituent member. In this review, we discuss the epichaperome, the cellular network that forms when the chaperome components of distinct chaperome machineries come together as stable, functionally integrated, multimeric complexes. In tumors, maintenance of the epichaperome network is vital for tumor survival, rendering them vulnerable to therapeutic interventions that target critical epichaperome network components. We discuss how the epichaperome empowers an approach for precision medicine cancer trials where a new target, biomarker, and relevant drug candidates can be correlated and integrated. We introduce chemical biology methods to investigate the heterogeneity of the chaperome in a given cellular context. Lastly, we discuss how ligand-protein binding kinetics are more appropriate than equilibrium binding parameters to characterize and unravel chaperome targeting in cancer and to gauge the selectivity of ligands for specific tumor-associated chaperome pools. This is the ninth article in the JBC Reviews series "Molecular chaperones and protein quality control." G. C. has partial ownership in Samus Therapeutics Inc., which develops epichaperome inhibitors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 1 Supported by the Lymphoma Research Foundation. 2 Supported by National Institutes of Health Grants R01 CA172546 and R01 CA102031 and the Irma T. Hirschl/Monique Weill-Caulier Trust and Unravel Pediatric Cancer Foundation.

A robust strategy for proteomic identification of biomarkers of invasive phenotype complexed with extracellular heat shock proteins

“…Interestingly, the clearest differentiation of HSP content was seen for distribution of inducible HSP70-1/2; while abundant in HEK293T, PSMs were not detected in equivalent eHSP of U87. Differentiation in HSP70 isoform representation may reflect specific features of tumorigenic phenotype and genetic stability, as recently determined by Chiosis group (Wang et al 2019). HSP60 was prominent in U87 and choriocarcinoma HELA and may be ratiometric of invasive phenotype (Caruso Bavisotto et al 2018) and inflammatory response (Kato and Svensson 2015).…”

“…Therefore, any opportunity to collect multiple secreted biomarkers afforded by robust HSP affinity enrichment is significant for translation to targeted clinical assays (Diamandis 2012). With regard to cumulative significance of extracellular HSP, in a survey of over 200 cancer cell cultures and primary isolates, Chiosis' group found that genetic stress rather than acute toxin treatment induced the most dramatic change in HSP profile as a stress-specific fingerprint (Wang et al 2019). For example, under toxic stress, HSP60 was recruited to the HSP90 chaperome network while genetic stress enlisted HSP70 isoforms.…”

“…Drugs that target cell surface HSPs are likely to become a common feature in oncology (Crouch et al 2017;Shevtsov et al 2018). HSP inhibitors are recognized as having substantial potential (Wang et al 2019;Neckers et al 2018). Furthermore, extracellular HSP profiles will allow differential diagnosis of other critical pathologies such as trauma, hyperthermia, and sepsis (Briassouli et al , 2015Briassoulis et al 2014;Vardas et al 2014).…”

The Unique Pharmacometrics of Small Molecule Therapeutic Drug Tracer Imaging for Clinical Oncology

“…Tumor avidity can be a diagnostic imaging biomarker of the molecular target to which the drug tracer binds in vivo. Tumor avidity for the isotopologue I-124 PU-H71 is a well-credentialed imaging biomarker of tumor epichaperome formations [ 49 , 68 ]. Epichaperomes are hyperconnected, integrated functional networks of chaperome units, induced by cellular stress as associated with malignancy [ 49 , 68 , 69 , 70 ].…”

Design of Disruptors of the Hsp90–Cdc37 Interface

“…In this context, specifically in higher organisms, given co-chaperones are able to load specific clients on Hsp90, modulating its activity in different cell tissues or along particular pathways [3]. Hsp90 and its co-chaperone systems are particularly overexpressed in transformed cells associated to disease states, especially cancer and neurodegeneration [4][5][6].…”