| Multiple myeloma, a malignant plasma cell infiltration of the bone marrow, is currently incurable: drug resistance inevitably arises from tumor cell-intrinsic and tumor microenvironment (TME)-mediated mechanisms. Here we report a novel pathway for myeloma drug resistance that is orchestrated by stromal secretion and processing of a matrix protein, HAPLN1 (hyaluronan and proteoglycan link protein 1). The HAPLN1 matrikine is secreted by bone marrow stromal cells, proteolyzed into fragments and two proteoglycan tandem repeat (PTR) domains 1/2 are retained in the TME. PTR1 (and other HAPLN1 fragments), but not full-length HAPLN1, activates NF-kappaB signaling, a well-known tumor driver for multiple myeloma. Furthermore, HAPLN1 activates the atypical NF-kappaB signaling pathway; since only the canonical NF-kappaB signaling pathway is inhibited by the clinical proteasome inhibitor, bortezomib, the matrikine therefore confers drug resistance. Additionally, HAPLN1-matrikine may also activate several other crucial signaling pathways involved in myeloma pathogenesis and confers drug resistance to several MM therapeutic drugs. However, Selinexor, a clinical-stage CRM1/XPO1 inhibitor, prevents matrikine-induced NF-kappaB activation and may create an opportunity to overcome drug-resistant multiple myeloma disease. |
