HAPLN1 confers multiple myeloma cell resistance to several classes of therapeutic drugs

Abstract

Multiple myeloma (MM), a malignant plasma cell infiltration of the bone marrow, is generally considered incurable: resistance to multiple therapeutic drugs inevitably arises from tumor cell-intrinsic and tumor microenvironment (TME)-mediated mechanisms. Here we report that the proteoglycan tandem repeat 1 (PTR1) domain of the TME matrix protein, hyaluronan and proteoglycan link protein 1 (HAPLN1), induces a host of cell survival genes in MM cells and variable resistance to different classes of clinical drugs, including certain proteasome inhibitors, steroids, immunomodulatory drugs, and DNA damaging agents, in several MM cell lines tested. Collectively, our study identifies HAPLN1 as an extracellular matrix factor that can simultaneously confer MM cell resistance to multiple therapeutic drugs.

HAPLN1 matrikine: a bone marrow homing factor linked to poor outcomes in patients with MM

“…We previously performed RNA sequencing (RNA-seq) analysis of RPMI8226 MM cells exposed to recombinant PTR1 (GSE202672) and identified NF-κB and JAK/STAT as potentially enriched signaling pathways. 14 We previously confirmed NF-κB activation, 12 but, to our knowledge, STAT activation has not been demonstrated by stimulation of MM cells with HAPLN1 matrikine. To further assess the potential involvement of STAT factors, we also evaluated the RNA-seq data using a novel bioinformatics tool, Mining Algorithm for GenetIc Controllers 21 and, again, identified NF-κB and STAT transcription factors as being among the top potential drivers of transcriptional changes in the HAPLN1 matrikine–induced genes ( Figure 3 A; supplemental Table 1 ).…”

“…We previously demonstrated that HAPLN1 matrikine can activate NF-κB signaling and induce NF-κB regulated drug resistance genes in MM cells. 12 , 14 This study showed peak NF-κB activation occurring within 2 hours after HAPLN1-PTR1 treatment in RPMI8226 cells, whereas peak STAT1 phosphorylation was delayed and observed 3 to 6 hours after stimulation. This temporal sequence suggests that STAT1 phosphorylation takes place after NF-κB activation.…”

“…To identify STAT1-dependent, migration-related genes whose expression was induced by HAPLN1 treatment, a similar RNA-seq analysis as previously done on RPMI8226 cells was performed, 14 except for using control and STAT1 KO cells ( supplemental Figure 3 E; GSE237216), the latter of which also showed defective MBP-PTR1–induced migration ( supplemental Figure 3 F). Cluster analysis identified 11 clusters in the differentially expressed genes ( supplemental Figure 3 G-H).…”

“… 11 Finally, proteolytic processing of hyaluronan and proteoglycan link protein 1 (HAPLN1) by matrix metalloproteinase 2, both secreted by BMSCs, produces HAPLN1 matrikine, which can cause NF-κB signaling and resistance of MM cells to several classes of anti-MM therapeutic agents. 12 , 13 , 14 In BM samples from patients with MM, variable levels of HAPLN1 matrikine forms could be detected. 12 Despite known roles in the regulation of both normal and cancer cell behaviors, a role of any matrikine in MM cell BM homing and ability in the prediction of poor patient outcomes remain unknown.…”

Hyaluronic Acid Interacting Molecules Mediated Crosstalk between Cancer Cells and Microenvironment from Primary Tumour to Distant Metastasis

“…Interestingly, decreased ITIH2 expression levels were associated with bortezomib resistance in multiple myeloma [160]. HAPLN1 induced multi-drug resistance to bortezomib and ixazomib in patients with multiple myeloma [161]. GC patients with high VCAN are often resistant to immunotherapy [149]; in one study, cervical cancer patients who were resistant to chemotherapy also presented high expression of VCAN [162].…”