Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo

Abstract

In most instances, multiple myeloma (MM) plasma cells (PCs) are reliant on factors made by cells of the bone marrow (BM) stroma for their survival and growth. To date, the nature and cellular composition of the BM tumor microenvironment and the critical factors which drive tumor progression remain imprecisely defined. Our studies show that Gremlin1 (Grem1), a highly conserved protein, which is abundantly secreted by a subset of BM mesenchymal stromal cells, plays a critical role in MM disease development. Analysis of human and mouse BM stromal samples by quantitative PCR showed that GREM1/Grem1 expression was significantly higher in the MM tumor-bearing cohorts compared to healthy controls (p < 0.05, Mann–Whitney test). Additionally, BM-stromal cells cultured with 5TGM1 MM PC line expressed significantly higher levels of Grem1, compared to stromal cells alone (p < 0.01, t-test), suggesting that MM PCs promote increased Grem1 expression in stromal cells. Furthermore, the proliferation of 5TGM1 MM PCs was found to be significantly increased when co-cultured with Grem1-overexpressing stromal cells (p < 0.01, t-test). To examine the role of Grem1 in MM disease in vivo, we utilized the 5TGM1/KaLwRij mouse model of MM. Our studies showed that, compared to immunoglobulin G (IgG) control antibody-treated mice, mice treated with an anti-Grem1 neutralizing antibody had a decrease in MM tumor burden of up to 81.2% (p < 0.05, two-way ANOVA). The studies presented here demonstrate, for the first time, a novel positive feedback loop between MM PCs and BM stroma, and that inhibiting this vicious cycle with a neutralizing antibody can dramatically reduce tumor burden in a preclinical mouse model of MM.

Bone Morphogenetic Protein Antagonist Gremlin-1 Increases Myofibroblast Transition in Dermal Fibroblasts: Implications for Systemic Sclerosis

“…IL-6 trans signaling, which is signaling using the soluble IL-6 receptor and IL-6 was found by us to induce collagen (O'Reilly et al, 2014) and we extended this further by demonstrating that IL-6-mediated-Gremlin-1 is facilitated through STAT3-as the STAT3 inhibitor S31-201 significantly retarded this effect. This is in keeping with our previous work (O'Reilly et al, 2014) and also recent work in lung fibrosis and most recently bone marrow-derived stromal cells were found to upregulate Gremlin-1 via IL-6 trans signaling and this could be retarded with the use of an IL-6 monoclonal antibody (Clark et al, 2020). Given the importance of IL-6 in SSc (O'Reilly et al, 2012(O'Reilly et al, , 2013, with significantly elevated levels in the blood and tissues (Hasegawa et al, 1999), a downstream target of IL-6 such as Gremlin-1 may be a more realistic target in this disease as the importance of IL-6 in normal immune functions is critical.…”

GREM1 signaling in cancer: tumor promotor and suppressor?

“…Inflammatory conditions such as osteoarthritis (Han et al 2016;Chang et al 2019) and renal inflammation (Lavoz et al 2015;Lavoz et al 2018) and damage are promoted by GREM1 overexpression, potentially via VEGFR2 signaling (Lavoz et al 2015). GREM1-mediated CREB and NFkB signaling has been proposed to increase to have anti-tumor effects in pre-clinical murine models of colorectal cancer (Kobayashi et al 2021) and multiple myeloma (Clark et al 2020). Transcenta have developed a monoclonal GREM1 antibody (TST003) that could inhibit GREM1-mediated activation of FGFR1 phosphorylation (Cheng et al 2022)…”

“…UCB has developed a human IgG4p monoclonal antibody called Ginisortamab that targets endogenous GREM1 and has been shown to neutralise its ability to antagonise BMP2 (Kobayashi et al 2021). Ginisortamab has been shown to have anti‐tumor effects in pre‐clinical murine models of colorectal cancer (Kobayashi et al 2021) and multiple myeloma (Clark et al 2020). Transcenta have developed a monoclonal GREM1 antibody (TST003) that could inhibit GREM1‐mediated activation of FGFR1 phosphorylation (Cheng et al 2022).…”

Myeloperoxidase creates a permissive microenvironmental niche for the progression of multiple myeloma

“…Despite recent advances in therapeutic strategies, patients will ultimately relapse, with only 50% of patients surviving 5 years following diagnosis 1,2 . While intrinsic genetic factors are known to play a key role in MM pathogenesis, recent studies have highlighted the critical role of the BM microenvironment in regulating immune evasion, disease progression and persistence 3–7 …”

“… 1 , 2 While intrinsic genetic factors are known to play a key role in MM pathogenesis, recent studies have highlighted the critical role of the BM microenvironment in regulating immune evasion, disease progression and persistence. 3 , 4 , 5 , 6 , 7 …”