Extracellular matrix protein Reelin promotes myeloma progression by facilitating tumor cell proliferation and glycolysis

Abstract

Reelin is an extracellular matrix protein that is crucial for neuron migration, adhesion, and positioning. We examined the expression of Reelin in a large cohort of multiple myeloma patients recorded in Gene Expression Omnibus (GEO) database and used over-expression and siRNA knockdown of Reelin to investigate the role of Reelin in myeloma cell growth. We find that Reelin expression is negatively associated with myeloma prognosis. Reelin promotes myeloma cell proliferation in vitro as well as in vivo. The Warburg effect, evidenced by increased glucose uptake and lactate production, is also enhanced in Reelin-expressing cells. The activation of FAK/Syk/Akt/mTOR and STAT3 pathways contributes to Reelin-induced cancer cell growth and metabolic reprogramming. Our findings further reveal that activated Akt and STAT3 pathways induce the upregulation of HIF1α and its downstream targets (LDHA and PDK1), leading to increased glycolysis in myeloma cells. Together, our results demonstrate the critical contributions of Reelin to myeloma growth and metabolism. It presents an opportunity for myeloma therapeutic intervention by inhibiting Reelin and its signaling pathways.

NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains

“…As shown in Fig. 2f, these changes are linked to the activation of oncogenes involved in multiple myeloma including SYK [43][44][45][46][47] , MET [48][49][50] and SH3GL3 51 in NSD2 overexpressing cells ( Fig. 2f).…”

A Prominent Couple

“…Downstream signaling events of Reelin involve recruitment of CRK and CRKL [110], and Src family tyrosine kinases, mediating subsequent activation of the PI3K/AKT pathway and inhibition of GSK3β [111,112]. Recently, the Src, STAT3 and AKT pathways, hyperactivated in NEPC, were shown to be stimulated by Reelin signaling in multiple myeloma corroborating the importance of Reelin signaling in NEPC [108,113]. Notably, Reelin induced upregulation of HIF1α in multiple myeloma, which has also been implicated in NEPC [108,114].…”

“…Recently, the Src, STAT3 and AKT pathways, hyperactivated in NEPC, were shown to be stimulated by Reelin signaling in multiple myeloma corroborating the importance of Reelin signaling in NEPC [108,113]. Notably, Reelin induced upregulation of HIF1α in multiple myeloma, which has also been implicated in NEPC [108,114]. Upregulation of Reelin signaling components (MAP1B, MAPK8IP1, NDEL1) in NEPC tissue has been identified by RNA-seq [9].…”

“…It is interesting to note that the extracellular glycoprotein and neuronal guidance molecule Reelin emerged as a central molecule in the regulatory network involving INSM1, L1CAM and REST. Reelin, commonly secreted by Cajal-Retzius cells in the developing nervous system, is increased in small cell lung cancer, retinoblastoma, esophageal cancer and multiple myeloma [105][106][107][108]. In PCa, a correlation between Reelin expression and Gleason score has been described [109].…”

“…cAMP further induced G1 growth arrest in LNCaP cell [104] and synergized with IL-6, a prominent inducer of NED [105]. IL-6 triggered REST repression and STAT3-induced NED in LNCaP cells [106][107][108]. Neuropeptides and IL-8 activated the nonreceptor tyrosine kinases ETK, Src and FAK resulting in androgenindependent AR activation [100,109].…”