title: Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells.
abstract: Disease relapse remains a major factor limiting the survival of cancer patients. In the plasma cell malignancy multiple myeloma (MM), nearly all patients ultimately succumb to disease relapse and progression despite new therapies that have improved remission rates. Tumor regrowth indicates that clonogenic growth potential is continually maintained, but the determinants of self-renewal in MM are not well understood. Normal stem cells are regulated by extrinsic niche factors, and the tumor microenvironment (TME) may similarly influence tumor cell clonogenic growth and self-renewal. Growth differentiation factor 15 (GDF15) is aberrantly secreted by bone marrow stromal cells (BMSCs) in MM. We found that GDF15 is produced by BMSCs after direct contact with plasma cells and enhances the tumor-initiating potential and self-renewal of MM cells in a protein kinase B- and SRY (sex-determining region Y)-box-dependent manner. Moreover, GDF15 induces the expansion of MM tumor-initiating cells (TICs), and changes in the serum levels of GDF15 were associated with changes in the frequency of clonogenic MM cells and the progression-free survival of MM patients. These findings demonstrate that GDF15 plays a critical role in mediating the interaction among mature tumor cells, the TME, and TICs, and strategies targeting GDF15 may affect long-term clinical outcomes in MM.
authors.affiliation: Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD;
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Tanno
authors.forename: Yiting
authors.initials: Y
authors.lastname: Lim
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Wang
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: Geoff
authors.initials: G
authors.lastname: Matthews
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Ghosh
authors.forename: Ivan
authors.initials: I
authors.lastname: Borrello
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Huff
authors.forename: William
authors.initials: W
authors.lastname: Matsui
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055436:Growth Differentiation Factor 15 / Q000097:blood / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D055436:Growth Differentiation Factor 15; D055748:SOXB1 Transcription Factors; D051057:Proto-Oncogene Proteins c-akt