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HSP90 inhibitors induce GPNMB cell-surface expression by modulating lysosomal positioning and sensitize breast cancer cells to glembatumumab vedotin

Oncogene volume 41, pages 1701–1717 (2022)Cite this article

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Abstract

Transmembrane glycoprotein NMB (GPNMB) is a prognostic marker of poor outcome in patients with triple-negative breast cancer (TNBC). Glembatumumab Vedotin, an antibody drug conjugate targeting GPNMB, exhibits variable efficacy against GPNMB-positive metastatic TNBC as a single agent. We show that GPNMB levels increase in response to standard-of-care and experimental therapies for multiple breast cancer subtypes. While these therapeutic stressors induce GPNMB expression through differential engagement of the MiTF family of transcription factors, not all are capable of increasing GPNMB cell-surface localization required for Glembatumumab Vedotin inhibition. Using a FACS-based genetic screen, we discovered that suppression of heat shock protein 90 (HSP90) concomitantly increases GPNMB expression and cell-surface localization. Mechanistically, HSP90 inhibition resulted in lysosomal dispersion towards the cell periphery and fusion with the plasma membrane, which delivers GPNMB to the cell surface. Finally, treatment with HSP90 inhibitors sensitizes breast cancers to Glembatumumab Vedotin in vivo, suggesting that combination of HSP90 inhibitors and Glembatumumab Vedotin may be a viable treatment strategy for patients with metastatic TNBC.

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Fig. 1: Standard-of-care and experimental treatments induce GPNMB expression in breast cancer cells.
Fig. 2: TFE3 regulates GPNMB expression in response to therapy-induced cell stress.
Fig. 3: Pharmacological inhibition of mTOR enhances GPNMB expression.
Fig. 4: Combination of Glembatumumab Vedotin with either MEK or mTOR inhibitors reduces TNBC growth.
Fig. 5: shRNA screen to identify novel modulators of cell-surface GPNMB expression.
Fig. 6: HSP90 inhibitors induce lysosomal scattering and fusion with the plasma membrane in MDA-MD-436 cells.
Fig. 7: HSP90 inhibitors increase lysosome proximity to the cell periphery and deliver GPNMB to the cell surface.
Fig. 8: A combination of HSP90 inhibition and Glembatumumab dramatically impairs the growth of TNBC cells in vivo.

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References

  1. Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26:1275–81.

    Article  PubMed  Google Scholar 

  2. Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486:395–9.

    Article  CAS  PubMed  Google Scholar 

  3. Damaskos C, Garmpi A, Nikolettos K, Vavourakis M, Diamantis E, Patsouras A, et al. Triple-negative breast cancer: the progress of targeted therapies and future tendencies. Anticancer Res. 2019;39:5285–96.

    Article  CAS  PubMed  Google Scholar 

  4. Rose AA, Grosset AA, Dong Z, Russo C, Macdonald PA, Bertos NR, et al. Glycoprotein nonmetastatic B is an independent prognostic indicator of recurrence and a novel therapeutic target in breast cancer. Clin Cancer Res. 2010;16:2147–56.

    Article  CAS  PubMed  Google Scholar 

  5. Yardley DA, Weaver R, Melisko ME, Saleh MN, Arena FP, Forero A, et al. EMERGE: a randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB-expressing breast cancer. J Clin Oncol. 2015;33:1609–19.

    Article  CAS  PubMed  Google Scholar 

  6. Chen C, Okita Y, Watanabe Y, Abe F, Fikry MA, Ichikawa Y, et al. Glycoprotein nmb is exposed on the surface of dormant breast cancer cells and induces stem cell-like properties. Cancer Res. 2018;78:6424–35.

    Article  CAS  PubMed  Google Scholar 

  7. Rose AAN, Biondini M, Curiel R, Siegel PM. Targeting GPNMB with glembatumumab vedotin: current developments and future opportunities for the treatment of cancer. Pharmacol Ther. 2017;179:127–41.

    Article  CAS  PubMed  Google Scholar 

  8. Tse KF, Jeffers M, Pollack VA, McCabe DA, Shadish ML, Khramtsov NV, et al. CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma. Clin Cancer Res. 2006;12:1373–82.

    Article  CAS  PubMed  Google Scholar 

  9. Bendell J, Saleh M, Rose AA, Siegel PM, Hart L, Sirpal S, et al. Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with locally advanced or metastatic breast cancer. J Clin Oncol. 2014;32:3619–25.

    Article  CAS  PubMed  Google Scholar 

  10. Vahdat LTF-TA, Schmid P, Blackwell K, Telli ML, Melisko M, Holgado E, et al. METRIC: A randomized international phase 2b study of the antibody-drug conjugate (ADC) glembatumumab vedotin (GV) in gpNMB-overexpressing, metastatic, triple-negative breast cancer (mTNBC) (Abstract P6-20-01.). Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018; San Antonio, TX Philadelphia (PA): AACR; Cancer Res 2019;79 4 Suppl.

  11. Ott PA, Pavlick AC, Johnson DB, Hart LL, Infante JR, Luke JJ, et al. A phase 2 study of glembatumumab vedotin, an antibody-drug conjugate targeting glycoprotein NMB, in patients with advanced melanoma. Cancer. 2019;125:1113–23.

    Article  CAS  PubMed  Google Scholar 

  12. Qian X, Mills E, Torgov M, LaRochelle WJ, Jeffers M. Pharmacologically enhanced expression of GPNMB increases the sensitivity of melanoma cells to the CR011-vcMMAE antibody-drug conjugate. Mol Oncol. 2008;2:81–93.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Rose AA, Annis MG, Frederick DT, Biondini M, Dong Z, Kwong L, et al. MAPK pathway inhibitors sensitize BRAF-mutant melanoma to an antibody-drug conjugate targeting GPNMB. Clin Cancer Res. 2016;22:6088–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006;10:515–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bergin ART, Loi S. Triple-negative breast cancer: recent treatment advances. F1000Res. 2019;8:1342.

  16. Cheng Y, Tian H. Current development status of MEK inhibitors. Molecules. 2017;22:1551.

  17. Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB, et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci USA. 2009;106:4519–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27:1160–7.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Liu H, Murphy CJ, Karreth FA, Emdal KB, White FM, Elemento O, et al. Identifying and targeting sporadic oncogenic genetic aberrations in mouse models of triple-negative breast cancer. Cancer Discov. 2018;8:354–69.

    Article  CAS  PubMed  Google Scholar 

  20. Jing J, Greshock J, Holbrook JD, Gilmartin A, Zhang X, McNeil E, et al. Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212. Mol Cancer Ther. 2012;11:720–9.

    Article  CAS  PubMed  Google Scholar 

  21. Slade L, Pulinilkunnil T. The MiTF/TFE family of transcription factors: master regulators of organelle signaling, metabolism, and stress adaptation. Mol Cancer Res. 2017;15:1637–43.

    Article  CAS  PubMed  Google Scholar 

  22. Raben N, Puertollano R. TFEB and TFE3: linking lysosomes to cellular adaptation to stress. Annu Rev Cell Dev Biol. 2016;32:255–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Martina JA, Puertollano R. Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. J Cell Biol. 2013;200:475–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Martina JA, Diab HI, Lishu L, Jeong AL, Patange S, Raben N, et al. The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris. Sci Signal. 2014;7:ra9.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Martina JA, Chen Y, Gucek M, Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy. 2012;8:903–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal. 2012;5:ra42.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Erdin S, et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. Embo J. 2012;31:1095–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hong SB, Oh H, Valera VA, Baba M, Schmidt LS, Linehan WM. Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization. PLoS ONE. 2010;5:e15793.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Hemesath TJ, Steingrímsson E, McGill G, Hansen MJ, Vaught J, Hodgkinson CA, et al. microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. Genes Dev. 1994;8:2770–80.

    Article  CAS  PubMed  Google Scholar 

  30. Pogenberg V, Ogmundsdóttir MH, Bergsteinsdóttir K, Schepsky A, Phung B, Deineko V, et al. Restricted leucine zipper dimerization and specificity of DNA recognition of the melanocyte master regulator MITF. Genes Dev. 2012;26:2647–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. DeRose YS, Wang G, Lin YC, Bernard PS, Buys SS, Ebbert MT, et al. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med. 2011;17:1514–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Le Borgne R, Planque N, Martin P, Dewitte F, Saule S, Hoflack B. The AP-3-dependent targeting of the melanosomal glycoprotein QNR-71 requires a di-leucine-based sorting signal. J Cell Sci. 2001;114:2831–41.

    Article  PubMed  Google Scholar 

  33. Starling GP, Yip YY, Sanger A, Morton PE, Eden ER, Dodding MP. Folliculin directs the formation of a Rab34-RILP complex to control the nutrient-dependent dynamic distribution of lysosomes. EMBO Rep. 2016;17:823–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schmidt LS, Linehan WM. FLCN: the causative gene for Birt-Hogg-Dubé syndrome. Gene. 2018;640:28–42.

    Article  CAS  PubMed  Google Scholar 

  35. Kong T, Ahn R, Yang K, Zhu X, Fu Z, Morin G, et al. CD44 promotes PD-L1 expression and its tumor-intrinsic function in breast and lung cancers. Cancer Res. 2020;80:444–57.

    Article  CAS  PubMed  Google Scholar 

  36. Xue Y, Meehan B, Macdonald E, Venneti S, Wang XQD, Witkowski L, et al. CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary. Nat Commun. 2019;10:558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li W, Xu H, Xiao T, Cong L, Love MI, Zhang F, et al. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol. 2014;15:554.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Jolly C, Morimoto RI. Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst. 2000;92:1564–72.

    Article  CAS  PubMed  Google Scholar 

  39. Giulino-Roth L, van Besien HJ, Dalton T, Totonchy JE, Rodina A, Taldone T, et al. Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma. Mol Cancer Ther. 2017;16:1779–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Agarraberes FA, Dice JF. A molecular chaperone complex at the lysosomal membrane is required for protein translocation. J Cell Sci. 2001;114:2491–9.

    Article  CAS  PubMed  Google Scholar 

  41. Bandyopadhyay U, Kaushik S, Varticovski L, Cuervo AM. The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. Mol Cell Biol. 2008;28:5747–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jongsma ML, Berlin I, Wijdeven RH, Janssen L, Janssen GM, Garstka MA, et al. An ER-associated pathway defines endosomal architecture for controlled cargo transport. Cell. 2016;166:152–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Woodford MR, Dunn DM, Blanden AR, Capriotti D, Loiselle D, Prodromou C, et al. The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. Nat Commun. 2016;7:12037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pick E, Kluger Y, Giltnane JM, Moeder C, Camp RL, Rimm DL, et al. High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res. 2007;67:2932–7.

    Article  CAS  PubMed  Google Scholar 

  45. Boshuizen J, Peeper DS. Rational cancer treatment combinations: an urgent clinical need. Mol Cell. 2020;78:1002–18.

    Article  CAS  PubMed  Google Scholar 

  46. van der Lienden MJC, Gaspar P, Boot R, Aerts J, van Eijk M. Glycoprotein non-metastatic protein B: an emerging biomarker for lysosomal dysfunction in macrophages. Int J Mol Sci. 2018;20:1.

    Google Scholar 

  47. Noda Y, Tsuruma K, Takata M, Ishisaka M, Tanaka H, Nakano Y, et al. GPNMB induces BiP expression by enhancing splicing of BiP Pre-mRNA during the endoplasmic reticulum stress response. Sci Rep. 2017;7:12160.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Martina JA, Puertollano R. TFEB and TFE3: The art of multi-tasking under stress conditions. Transcription. 2017;8:48–54.

    Article  CAS  PubMed  Google Scholar 

  49. Tanaka M, Homme M, Yamazaki Y, Shimizu R, Takazawa Y, Nakamura T. Modeling alveolar soft part sarcoma unveils novel mechanisms of metastasis. Cancer Res. 2017;77:897–907.

    Article  CAS  PubMed  Google Scholar 

  50. Zhitomirsky B, Assaraf YG. Lysosomal sequestration of hydrophobic weak base chemotherapeutics triggers lysosomal biogenesis and lysosome-dependent cancer multidrug resistance. Oncotarget. 2015;6:1143–56.

    Article  PubMed  Google Scholar 

  51. Li B, Castano AP, Hudson TE, Nowlin BT, Lin SL, Bonventre JV, et al. The melanoma-associated transmembrane glycoprotein Gpnmb controls trafficking of cellular debris for degradation and is essential for tissue repair. Faseb J. 2010;24:4767–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 2013;4:e838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, et al. TFEB links autophagy to lysosomal biogenesis. Science. 2011;332:1429–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Vega-Rubin-de-Celis S, Peña-Llopis S, Konda M, Brugarolas J. Multistep regulation of TFEB by MTORC1. Autophagy. 2017;13:464–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Puertollano R, Ferguson SM, Brugarolas J, Ballabio A. The complex relationship between TFEB transcription factor phosphorylation and subcellular localization. Embo J. 2018;37:e98804.

  56. Martina JA, Diab HI, Brady OA, Puertollano R. TFEB and TFE3 are novel components of the integrated stress response. Embo J. 2016;35:479–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wada S, Neinast M, Jang C, Ibrahim YH, Lee G, Babu A, et al. The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue. Genes Dev. 2016;30:2551–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hoffmann RM, Coumbe BGT, Josephs DH, Mele S, Ilieva KM, Cheung A, et al. Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs). Oncoimmunology. 2018;7:e1395127.

    Article  PubMed  Google Scholar 

  59. Wang H, Lu M, Yao M, Zhu W. Effects of treatment with an Hsp90 inhibitor in tumors based on 15 phase II clinical trials. Mol Clin Oncol. 2016;5:326–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jansson KH, Tucker JB, Stahl LE, Simmons JK, Fuller C, Beshiri ML, et al. High-throughput screens identify HSP90 inhibitors as potent therapeutics that target inter-related growth and survival pathways in advanced prostate cancer. Sci Rep. 2018;8:17239.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Bekki H, Kohashi K, Maekawa A, Yamada Y, Yamamoto H, Harimaya K, et al. Elevated expression of HSP90 and the antitumor effect of an HSP90 inhibitor via inactivation of the Akt/mTOR pathway in undifferentiated pleomorphic sarcoma. BMC Cancer. 2015;15:804.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Butler LM, Ferraldeschi R, Armstrong HK, Centenera MM, Workman P. Maximizing the therapeutic potential of HSP90 inhibitors. Mol Cancer Res. 2015;13:1445–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dai C. The heat-shock, or HSF1-mediated proteotoxic stress, response in cancer: from proteomic stability to oncogenesis. Philos Trans R Soc Lond B Biol Sci. 2018;373:20160525.

  64. Wang Y, McAlpine SR. N-terminal and C-terminal modulation of Hsp90 produce dissimilar phenotypes. Chem Commun. 2015;51:1410–3.

    Article  CAS  Google Scholar 

  65. Pu J, Guardia CM, Keren-Kaplan T, Bonifacino JS. Mechanisms and functions of lysosome positioning. J Cell Sci. 2016;129:4329–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kallunki T, Olsen OD, Jäättelä M. Cancer-associated lysosomal changes: friends or foes? Oncogene. 2013;32:1995–2004.

    Article  CAS  PubMed  Google Scholar 

  67. Petit CS, Roczniak-Ferguson A, Ferguson SM. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J Cell Biol. 2013;202:1107–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. El-Houjeiri L, Possik E, Vijayaraghavan T, Paquette M, Martina JA, Kazan JM, et al. The transcription factors TFEB and TFE3 link the FLCN-AMPK signaling axis to innate immune response and pathogen resistance. Cell Rep. 2019;26:3613–28.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lauwers E, Wang YC, Gallardo R, Van der Kant R, Michiels E, Swerts J, et al. Hsp90 mediates membrane deformation and exosome release. Mol Cell. 2018;71:689–702.e9.

    Article  CAS  PubMed  Google Scholar 

  70. Park S, Park JA, Jeon JH, Lee Y. Traditional and novel mechanisms of heat shock protein 90 (HSP90) inhibition in cancer chemotherapy including HSP90 cleavage. Biomol Ther. 2019;27:423–34.

    Article  CAS  Google Scholar 

  71. Kopp LM, Malempati S, Krailo M, Gao Y, Buxton A, Weigel BJ, et al. Phase II trial of the glycoprotein non-metastatic B-targeted antibody-drug conjugate, glembatumumab vedotin (CDX-011), in recurrent osteosarcoma AOST1521: a report from the Children’s Oncology Group. Eur J Cancer. 2019;121:177–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Nytko KJ, Thumser-Henner P, Russo G, Weyland MS, Rohrer Bley C. Role of HSP70 in response to (thermo)radiotherapy: analysis of gene expression in canine osteosarcoma cells by RNA-seq. Sci Rep. 2020;10:12779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. El-Houjeiri L, Biondini M, Paquette M, Kuasne H, Pacis A, Park M, et al. Folliculin impairs breast tumor growth by repressing TFE3-dependent induction of the Warburg effect and angiogenesis. J Clin Investig. 2021;131:e144871.

  74. McGuirk S, Audet-Delage Y, Annis MG, Xue Y, Vernier M, Zhao K, et al. Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer. Elife. 2021;10:e65150.

  75. Sirois I, Aguilar-Mahecha A, Lafleur J, Fowler E, Vu V, Scriver M, et al. A unique morphological phenotype in chemoresistant triple-negative breast cancer reveals metabolic reprogramming and PLIN4 expression as a molecular vulnerability. Mol Cancer Res. 2019;17:2492–507.

    Article  CAS  PubMed  Google Scholar 

  76. Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014;508:118–22.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge technical assistance from the McGill GCRC Histology core facility for routine histological services. We acknowledge McGill Life Science Complex Advanced BioImaging Facility (ABIF) for technical assistance in acquisition/analysis of images. We acknowledge McGill Platform for Cellular Perturbation (MPCP) for providing the shRNAs libraries and technical assistance with screnning process and analysis. We acknowledge McGill Life Science Complex Cell Vision Core for technical assistance in acquisition/analysis of flow cytometry data. We acknowledge Génome Quebec and McGill University for support of the Q-CROC-03 trial. We acknowledge Dr. Alana Welm for providing us with HCI-010 PDX tumor model. We thank members of the Siegel laboratory, all collaborators and Dr. Ursini-Siegel for thoughtful discussions and critical reading of the paper. MB was the recipient of a Fonds de recherche du Québec—Santé (FRQS) post-doctoral fellowship. PMS is a William Dawson Scholar of McGill University. This work was supported by an operating grant from the Canadian Institutes of Health Research to PMS (PJT-153327).

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Authors and Affiliations

  1. Goodman Cancer Research Institute, McGill University, Montreal, QC, Canada

    Marco Biondini, Alex Kiepas, Leeanna El-Houjeiri, Matthew G. Annis, Brian E. Hsu, Anne-Marie Fortier, Geneviève Morin, Tina Gruosso, Shawn McGuirk, Morag Park, Arnim Pause, Sidong Huang & Peter M. Siegel

  2. Department of Medicine, McGill University, Montreal, QC, Canada

    Marco Biondini, Matthew G. Annis, Brian E. Hsu, Morag Park, Arnim Pause & Peter M. Siegel

  3. Department of Physiology, McGill University, Montreal, QC, Canada

    Alex Kiepas & Shawn McGuirk

  4. Department of Biochemistry, McGill University, Montreal, QC, Canada

    Leeanna El-Houjeiri, Anne-Marie Fortier, Geneviève Morin, Tina Gruosso, Morag Park, Sidong Huang & Peter M. Siegel

  5. Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA

    José A. Martina & Rosa Puertollano

  6. Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, QC, Canada

    Isabelle Sirois, Adriana Aguilar-Mahecha & Mark Basik

  7. Department of Oncology and Surgery, McGill University, Montreal, QC, Canada

    April A. N. Rose & Mark Basik

  8. Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey

    Unal M. Tokat

  9. 1 DNA Way South, Genentech, San Francisco, CA, USA

    Radia M. Johnson

  10. Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, USA

    Ozgur Sahin

  11. Genome Québec Innovation Center, McGill University, Montreal, QC, Canada

    Eric Bareke & Jacek Majewski

  12. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Eric Bareke & Jacek Majewski

  13. Department of Biochemistry, Microbiology and Immunology and Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada

    Julie St-Pierre

  14. Celldex Therapeutics, Hampton, NJ, USA

    Tibor Keler

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  1. Marco Biondini
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Contributions

MB and PMS designed the research. MB, AK, MGA, BEH, JAM, GM, and LE performed experiments. AANR, AAM, TG, RMJ, GM, and EB, performed computational analysis, statistical analysis, biostatistics. IS, AAM, SM, JSP, UMT, MB, RP, OS, SH, TK, and AP, provided reagents and expertise. MB and PMS wrote the paper.

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Correspondence to Peter M. Siegel.

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Biondini, M., Kiepas, A., El-Houjeiri, L. et al. HSP90 inhibitors induce GPNMB cell-surface expression by modulating lysosomal positioning and sensitize breast cancer cells to glembatumumab vedotin. Oncogene 41, 1701–1717 (2022). https://doi.org/10.1038/s41388-022-02206-z

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  • DOI: https://doi.org/10.1038/s41388-022-02206-z

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