Multiple myeloma gammopathies

Dynamic CD138 surface expression regulates switch between myeloma growth and dissemination

Article metrics


The canonical plasma cell marker CD138 (syndecan-1) is highly expressed on the myeloma cell surface, but its functional role in vivo is unclear, as well as the ontogeny of CD138-high and CD138-negative (neg) myeloma cells. In this study we used an in vivo murine Vk*MYC myeloma model where CD138 is heterogeneously expressed depending on tumor size. We find that in comparison to CD138-neg myeloma cells, the CD138-high subset of myeloma cells is highly proliferative, less apoptotic, and enhanced IL-6R signaling, which is known to promote survival. In addition CD138-high myeloma engrafts better than its CD138-neg counterpart. In contrast, CD138-neg cells are more motile both in vitro and in vivo, and more readily disseminate and spread to other bones in vivo than CD138-high subset. Neutralizing CD138 rapidly triggers migration of myeloma cells in vivo and leads to intravasation, which results in increased dissemination to other bones. Both murine and human myeloma cells can rapidly recycle CD138 surface expression through endocytic trafficking, in response to serum levels. Blocking CD138 enhances myeloma sensitivity to bortezomib chemotherapy and significantly reduces tumor size compared to bortezomib treatment alone. Thus, our data show that CD138 surface expression dynamically regulates a switch between growth vs. dissemination for myeloma, in response to nutrient conditions.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. 1.

    Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122–8.

  2. 2.

    Boise LH, Kaufman JL, Bahlis NJ, Lonial S, Lee KP. The Tao of myeloma. Blood. 2014;124:1873–9.

  3. 3.

    Fairfield H, Falank C, Avery L, Reagan MR. Multiple myeloma in the marrow: pathogenesis and treatments. Ann N Y Acad Sci. 2016;1364:32–51.

  4. 4.

    Di Marzo L, Desantis V, Solimando AG, Ruggieri S, Annese T, Nico B, et al. Microenvironment drug resistance in multiple myeloma: emerging new players. Oncotarget. 2016;7:60698–711.

  5. 5.

    Roccaro AM, Sacco A, Purschke WG, Moschetta M, Buchner K, Maasch C, et al. SDF-1 inhibition targets the bone marrow niche for cancer therapy. Cell Rep. 2014;9:118–28.

  6. 6.

    Azab AK, Runnels JM, Pitsillides C, Moreau AS, Azab F, Leleu X, et al. CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood. 2009;113:4341–51.

  7. 7.

    Rollig C, Knop S, Bornhauser M. Multiple myeloma. Lancet. 2015;385:2197–208.

  8. 8.

    Stepp MA, Gibson HE, Gala PH, Iglesia DD, Pajoohesh-Ganji A, Pal-Ghosh S, et al. Defects in keratinocyte activation during wound healing in the syndecan-1-deficient mouse. J Cell Sci. 2002;115:4517–31.

  9. 9.

    Koda JE, Rapraeger A, Bernfield M. Heparan sulfate proteoglycans from mouse mammary epithelial cells. Cell surface proteoglycan as a receptor for interstitial collagens. J Biol Chem. 1985;260:8157–62.

  10. 10.

    Freissler E, Meyer auf der Heyde A, David G, Meyer TF, Dehio C. Syndecan-1 and syndecan-4 can mediate the invasion of OpaHSPG-expressing Neisseria gonorrhoeae into epithelial cells. Cell Microbiol. 2000;2:69–82.

  11. 11.

    Yao W, Rose JL, Wang W, Seth S, Jiang H, Taguchi A, et al. Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer. Nature. 2019;568:410–4.

  12. 12.

    Stewart MD, Ramani VC, Sanderson RD. Shed syndecan-1 translocates to the nucleus of cells delivering growth factors and inhibiting histone acetylation: a novel mechanism of tumor-host cross-talk. J Biol Chem. 2015;290:941–9.

  13. 13.

    Beauvais DM, Ell BJ, McWhorter AR, Rapraeger AC. Syndecan-1 regulates alphavbeta3 and alphavbeta5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor. J Exp Med. 2009;206:691–705.

  14. 14.

    Rapraeger AC. Syndecan-regulated receptor signaling. J Cell Biol. 2000;149:995–8.

  15. 15.

    Coombe DR. Biological implications of glycosaminoglycan interactions with haemopoietic cytokines. Immunol Cell Biol. 2008;86:598–607.

  16. 16.

    Casu B, Naggi A, Torri G. Heparin-derived heparan sulfate mimics to modulate heparan sulfate-protein interaction in inflammation and cancer. Matrix Biol. 2010;29:442–52.

  17. 17.

    Bernfield M, Gotte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J, et al. Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem. 1999;68:729–77.

  18. 18.

    Hayashida K, Bartlett AH, Chen Y, Park PW. Molecular and cellular mechanisms of ectodomain shedding. Anat Rec. 2010;293:925–37.

  19. 19.

    Lonial S, Durie B, Palumbo A, San-Miguel J. Monoclonal antibodies in the treatment of multiple myeloma: current status and future perspectives. Leukemia. 2016;30:526–35.

  20. 20.

    Polson AG, Sliwkowski MX. Toward an effective targeted chemotherapy for multiple myeloma. Clinical cancer research: an official journal of the American Association for. Cancer Res. 2009;15:3906–7.

  21. 21.

    Yoo EM, Trinh KR, Tran D, Vasuthasawat A, Zhang J, Hoang B, et al. Anti-CD138-targeted interferon is a potent therapeutic against multiple myeloma. J Interferon Cytokine Res. 2015;35:281–91.

  22. 22.

    McCarron MJ, Park PW, Fooksman DR. CD138 mediates selection of mature plasma cells by regulating their survival. Blood. 2017;129:2749–59.

  23. 23.

    Reijmers RM, Spaargaren M, Pals ST. Heparan sulfate proteoglycans in the control of B cell development and the pathogenesis of multiple myeloma. FEBS J. 2013;280:2180–93.

  24. 24.

    Khotskaya YB, Dai Y, Ritchie JP, MacLeod V, Yang Y, Zinn K, et al. Syndecan-1 is required for robust growth, vascularization, and metastasis of myeloma tumors in vivo. J Biol Chem. 2009;284:26085–95.

  25. 25.

    Moreaux J, Sprynski AC, Dillon SR, Mahtouk K, Jourdan M, Ythier A, et al. APRIL and TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop. Eur J Haematol. 2009;83:119–29.

  26. 26.

    Derksen PW, de Gorter DJ, Meijer HP, Bende RJ, van Dijk M, Lokhorst HM, et al. The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma. Leukemia. 2003;17:764–74.

  27. 27.

    Mahtouk K, Cremer FW, Reme T, Jourdan M, Baudard M, Moreaux J, et al. Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma. Oncogene. 2006;25:7180–91.

  28. 28.

    Beauvais DM, Jung O, Yang Y, Sanderson RD, Rapraeger AC. Syndecan-1 (CD138) Suppresses Apoptosis in Multiple Myeloma by Activating IGF1 Receptor: Prevention by SynstatinIGF1R Inhibits Tumor Growth. Cancer Res. 2016;76:4981–93.

  29. 29.

    Wu YH, Yang CY, Chien WL, Lin KI, Lai MZ. Removal of syndecan-1 promotes TRAIL-induced apoptosis in myeloma cells. J Immunol. 2012;188:2914–21.

  30. 30.

    Jourdan M, Ferlin M, Legouffe E, Horvathova M, Liautard J, Rossi JF, et al. The myeloma cell antigen syndecan-1 is lost by apoptotic myeloma cells. Br J Haematol. 1998;100:637–46.

  31. 31.

    Seidel C, Borset M, Hjertner O, Cao D, Abildgaard N, Hjorth-Hansen H, et al. High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity. Blood. 2000;96:3139–46.

  32. 32.

    Kawano Y, Fujiwara S, Wada N, Izaki M, Yuki H, Okuno Y, et al. Multiple myeloma cells expressing low levels of CD138 have an immature phenotype and reduced sensitivity to lenalidomide. Int J Oncol. 2012;41:876–84.

  33. 33.

    Ghosh N, Matsui W. Cancer stem cells in multiple myeloma. Cancer Lett. 2009;277:1–7.

  34. 34.

    Paino T, Sarasquete ME, Paiva B, Krzeminski P, San-Segundo L, Corchete LA, et al. Phenotypic, genomic and functional characterization reveals no differences between CD138++ and CD138low subpopulations in multiple myeloma cell lines. PloS ONE. 2014;9:e92378

  35. 35.

    Chaidos A, Barnes CP, Cowan G, May PC, Melo V, Hatjiharissi E, et al. Clinical drug resistance linked to interconvertible phenotypic and functional states of tumor-propagating cells in multiple myeloma. Blood. 2013;121:318–28.

  36. 36.

    Chesi M, Robbiani DF, Sebag M, Chng WJ, Affer M, Tiedemann R, et al. AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell. 2008;13:167–80.

  37. 37.

    Chesi M, Matthews GM, Garbitt VM, Palmer SE, Shortt J, Lefebure M, et al. Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy. Blood. 2012;120:376–85.

  38. 38.

    Chesi M, Mirza NN, Garbitt VM, Sharik ME, Dueck AC, Asmann YW, et al. IAP antagonists induce anti-tumor immunity in multiple myeloma. Nat Med. 2016.

  39. 39.

    Jensen JL, Rakhmilevich A, Heninger E, Broman AT, Hope C, Phan F, et al. Tumoricidal effects of macrophage-activating immunotherapy in a murine model of relapsed/refractory multiple myeloma. Cancer Immunol Res. 2015;3:881–90.

  40. 40.

    Alexander CM, Reichsman F, Hinkes MT, Lincecum J, Becker KA, Cumberledge S, et al. Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice. Nat Genet. 2000;25:329–32.

  41. 41.

    Teng YH, Aquino RS, Park PW. Molecular functions of syndecan-1 in disease. Matrix Biol: J Int Soc Format Biol. 2012;31:3–16.

  42. 42.

    Frigyesi I, Adolfsson J, Ali M, Christophersen MK, Johnsson E, Turesson I, et al. Robust isolation of malignant plasma cells in multiple myeloma. Blood. 2014;123:1336–40.

  43. 43.

    Leung-Hagesteijn C, Erdmann N, Cheung G, Keats JJ, Stewart AK, Reece DE, et al. Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell. 2013;24:289–304.

  44. 44.

    Rasche L, Chavan SS, Stephens OW, Patel PH, Tytarenko R, Ashby C, et al. Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. Nat Commun. 2017;8:268

  45. 45.

    Mithraprabhu S, Khong T, Ramachandran M, Chow A, Klarica D, Mai L, et al. Circulating tumour DNA analysis demonstrates spatial mutational heterogeneity that coincides with disease relapse in myeloma. Leukemia. 2017;31:1695–705.

  46. 46.

    Ikeda H, Hideshima T, Fulciniti M, Lutz RJ, Yasui H, Okawa Y, et al. The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin Cancer Res. 2009;15:4028–37.

Download references


This work was supported by the National Institutes of Health and Einstein start-up funds. We would like to thank Jeff Segall for critical feedback, Sonia Elhadad for preliminary studies and technical assistance.

Author information

MJM, IA, and DRF performed the experiments. DRF designed the research and wrote the paper. MC and PLB developed Vk*MYC system and provided key insights. SP provided the human samples, and key insights.

Correspondence to David R. Fooksman.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading