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Characterizing dry mass and volume changes in human multiple myeloma cells upon treatment with proteotoxic and genotoxic drugs

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Abstract

Multiple myeloma (MM) is a cancer of terminally differentiated plasma cells. MM remains incurable, but overall survival of patients has progressively increased over the past two decades largely due to novel agents such as proteasome inhibitors (PI) and the immunomodulatory agents. While these therapies are highly effective, MM patients can be de novo resistant and acquired resistance with prolonged treatment is inevitable. There is growing interest in early, accurate identification of responsive versus non-responsive patients; however, limited sample availability and need for rapid assays are limiting factors. Here, we test dry mass and volume as label-free biomarkers to monitor early response of MM cells to treatment with bortezomib, doxorubicin, and ultraviolet light. For the dry mass measurement, we use two types of phase-sensitive optical microscopy techniques: digital holographic tomography and computationally enhanced quantitative phase microscopy. We show that human MM cell lines (RPMI8226, MM.1S, KMS20, and AMO1) increase dry mass upon bortezomib treatment. This dry mass increase after bortezomib treatment occurs as early as 1 h for sensitive cells and 4 h for all tested cells. We further confirm this observation using primary multiple myeloma cells derived from patients and show that a correlation exists between increase in dry mass and sensitivity to bortezomib, supporting the use of dry mass as a biomarker. The volume measurement using Coulter counter shows a more complex behavior; RPMI8226 cells increase the volume at an early stage of apoptosis, but MM.1S cells show the volume decrease typically observed with apoptotic cells. Altogether, this cell study presents complex kinetics of dry mass and volume at an early stage of apoptosis, which may serve as a basis for the detection and treatment of MM cells.

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References

  1. Bianchi G, Munshi NC. Pathogenesis beyond the cancer clone (s) in multiple myeloma. Blood. 2015;125:3049–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. SEER Cancer Statistics Factsheets: Myeloma [Internet]. https://seer.cancer.gov/statfacts/html/mulmy.html

  3. Bianchi G, Anderson KC. Understanding biology to tackle the disease: Multiple myeloma from bench to bedside, and back. CA Cancer J Clin. 2014;6:422–44.

    Article  Google Scholar 

  4. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487–98.

    Article  CAS  PubMed  Google Scholar 

  5. Guang MHZ, McCann A, Bianchi G, et al. Overcoming multiple myeloma drug resistance in the era of cancer ‘omics.’ Leuk Lymphoma. 2018;59:542–61.

    Article  CAS  PubMed  Google Scholar 

  6. Anderson KC. Bench-to-bedside translation of targeted therapies in multiple myeloma. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30:445.

    Article  CAS  Google Scholar 

  7. Bianchi G, Oliva L, Cascio P, et al. The proteasome load vs. capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition. Blood. 2009;113:3040–9.

    Article  CAS  PubMed  Google Scholar 

  8. Barer R, Ross KFA, Tkaczyk S. Refractometry of living cells. Nature. 1953;171:720–4.

    Article  CAS  PubMed  Google Scholar 

  9. Zhao H, Brown PH, Schuck P. On the distribution of protein refractive index increments. Biophys J. 2011;100:2309–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sung Y, Tzur A, Oh S, et al. Size homeostasis in adherent cells studied by synthetic phase microscopy. Proc Natl Acad Sci. 2013;110:16687–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liu X, Oh S, Peshkin L, Kirschner MW. Computationally enhanced quantitative phase microscopy reveals autonomous oscillations in mammalian cell growth. Proc Natl Acad Sci Nat Acad Sci. 2020;117:27388–99.

    Article  CAS  Google Scholar 

  12. Lines RW. The Electrical sensing zone method (The Coulter Principle). In: Stanley-Wood NG, Lines RW, editors. Particle size analysis. London: Royal Society of Chemistry; 1992. p. 350–73.

    Chapter  Google Scholar 

  13. Charrière F, Marian A, Montfort F, et al. Cell refractive index tomography by digital holographic microscopy. Opt Lett. 2006;31:178–80.

    Article  PubMed  Google Scholar 

  14. Choi W, Fang-Yen C, Badizadegan K, et al. Tomographic phase microscopy. Nat Methods. 2007;4:717.

    Article  CAS  PubMed  Google Scholar 

  15. Bon P, Aknoun S, Savatier J, Wattellier B, Monneret S. Tomographic incoherent phase imaging, a diffraction tomography alternative for any white-light microscope. Three-dimens multidimens microsc image acquis process XX. Proc SPIE. 2013;8589:179.

    Google Scholar 

  16. Kim T, Zhou R, Mir M, et al. White-light diffraction tomography of unlabelled live cells. Nat Photonics. 2014;8:256.

    Article  CAS  Google Scholar 

  17. Glass GV, Smith ML, McGaw B. Meta analysis in social research. Beverly Hills: Sage Publications; 1981.

    Google Scholar 

  18. Belmokhtar CA, Hillion J, Ségal-Bendirdjian E. Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms. Oncogene. 2001;20:3354–62.

    Article  CAS  PubMed  Google Scholar 

  19. Cenci S, Oliva L, Cerruti F, et al. Pivotal advance: protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors. J Leukoc Biol. 2012;92:921–31.

    Article  CAS  PubMed  Google Scholar 

  20. Paramore A, Frantz S. Bortezomib. Nat Rev Drug Discov. 2003;2:611.

    Article  CAS  PubMed  Google Scholar 

  21. Hurley LH. DNA and its associated processes as targets for cancer therapy. Nat Rev Cancer. 2002;2:188.

    Article  CAS  PubMed  Google Scholar 

  22. Davies RJH. Ultraviolet radiation damage in DNA. Biochem Soc Trans. 1995;23:407–18.

    Article  CAS  PubMed  Google Scholar 

  23. Platonova A, Koltsova SV, Hamet P, Grygorczyk R, Orlov SN. Swelling rather than shrinkage precedes apoptosis in serum-deprived vascular smooth muscle cells. Apoptosis. 2012;17:429–38.

    Article  CAS  PubMed  Google Scholar 

  24. Kasim NR, Kuželová K, Holoubek A, Model MA. Live fluorescence and transmission-through-dye microscopic study of actinomycin D-induced apoptosis and apoptotic volume decrease. Apoptosis. 2013;18:521–32.

    Article  CAS  PubMed  Google Scholar 

  25. Bortner CD, Cidlowski JA. Uncoupling cell shrinkage from apoptosis reveals that Na+ influx is required for volume loss during programmed cell death. J Biol Chem. 2003;278:39176–84.

    Article  CAS  PubMed  Google Scholar 

  26. Yurinskaya V, Goryachaya T, Guzhova I, et al. Potassium and sodium balance in U937 cells during apoptosis with and without cell shrinkage. Cell Physiol Biochem. 2005;16:155–62.

    Article  CAS  PubMed  Google Scholar 

  27. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35:495–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge the late professor Michael Feld for initiating this research. Some early findings reported in this article were published in the Ph.D. dissertation (MIT, 2011) by Yongjin Sung. The authors thank Professor Marc Kirschner of Harvard Medical School for making available the ceQPM microscope and analytical tools.

Funding

This work was funded by the National Institutes of Health (P41EB015871-33, R01GM026875, ZY, YS; R56AG073341, XL, SO; 5K08CA245100, GB), the National Science Foundation (DBI-0754339, ZY, YS), and Hamamatsu Photonics, Japan, (ZY, YS).

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Author notes

  1. Xili Liu and Maria Moscvin have equally contributed to this work.

  2. Giada Bianchi and Yongjin Sung have equally contributed to this work.

Authors and Affiliations

  1. Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA

    Xili Liu & Seungeun Oh

  2. Amyloidosis Program, Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Maria Moscvin, Tianzeng Chen, Benjamin Evans & Giada Bianchi

  3. Department of Physics, Korea University, Seoul, Korea

    Wonshik Choi

  4. Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, MA, 02115, USA

    Sean M. Rowell, Omar Nadeem, Clifton C. Mo & Kenneth C. Anderson

  5. Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Adam S. Sperling

  6. Laser Biomedical Research Center, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Zahid Yaqoob

  7. College of Engineering and Applied Science, University of Wisconsin, Milwaukee, WI, 53211, USA

    Yongjin Sung

Authors
  1. Xili Liu
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  2. Maria Moscvin
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  3. Seungeun Oh
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  4. Tianzeng Chen
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  6. Benjamin Evans
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  7. Sean M. Rowell
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  8. Omar Nadeem
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  11. Kenneth C. Anderson
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  12. Zahid Yaqoob
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  13. Giada Bianchi
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  14. Yongjin Sung
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Contributions

WC, KCA GB and YS developed the concept; XL, WC, GB and YS designed the experiments; XL, MM, SO, TC, BE, GB and YS performed the experiments; XL, MM, SO, WC, TC, BE, ZY, GB and YS analyzed the data; SMR, ON, CCM, ASS and GB contributed primary samples; ZY and GB secured funding for research; XL, GB and YS wrote the manuscript; all authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Giada Bianchi or Yongjin Sung.

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Conflict of interest

OM serves on the advisory committees of Karyopharm, Adaptive Biotechnologies, Takeda, Bristol Myers Squibb (BMS) and GlaxoSmithKline (GSK). CMM has received honoraria and/or serves on the advisory committees of Sanofi, GSK, BMS, Epizyme, Eli Lilly, Janssen and Karyopharm. ASS serves as a consultant for Adaptive Biotechnologies. KCA serves on advisory boards to Takeda, Janssen, Sanofi-Aventis, BMS, Celgene, Gilead, Pfizer, Astrazeneca, Mana Therapeutics, and is a Scientific Founder of OncoPep and C4 Therapeutics. GB received honoraria for consulting from Karyopharm and Pfizer. All other authors declare no conflict of interest.

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Liu, X., Moscvin, M., Oh, S. et al. Characterizing dry mass and volume changes in human multiple myeloma cells upon treatment with proteotoxic and genotoxic drugs. Clin Exp Med 23, 3821–3832 (2023). https://doi.org/10.1007/s10238-023-01124-y

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