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. 2023 Dec;17(4):1517-1526.
doi: 10.1007/s12079-023-00777-4. Epub 2023 Aug 24.

GREM1 signaling in cancer: tumor promotor and suppressor?

Zhichun Gao  1 , Julia M Houthuijzen  2 , Peter Ten Dijke  3 , Derek P Brazil  4
Affiliations

GREM1 signaling in cancer: tumor promotor and suppressor?

Zhichun Gao et al. J Cell Commun Signal. 2023 Dec.

Abstract

GREMLIN1 (GREM1) is member of a family of structurally and functionally related secreted cysteine knot proteins, which act to sequester and inhibit the action of multifunctional bone morphogenetic proteins (BMPs). GREM1 binds directly to BMP dimers, thereby preventing BMP-mediated activation of BMP type I and type II receptors. Multiple reports identify the overexpression of GREM1 as a contributing factor in a broad range of cancers. Additionally, the GREM1 gene is amplified in a rare autosomal dominant inherited form of colorectal cancer. The inhibitory effects of GREM1 on BMP signaling have been linked to these tumor-promoting effects, including facilitating cancer cell stemness and the activation of cancer-associated fibroblasts. Moreover, GREM1 has been described to bind and signal to vascular endothelial growth factor receptor (VEGFR) and stimulate angiogenesis, as well as epidermal and fibroblast growth factor receptor (EGFR and FGFR) to elicit tumor-promoting effects in breast and prostate cancer, respectively. In contrast, a 2022 report revealed that GREM1 can promote an epithelial state in pancreatic cancers, thereby inhibiting pancreatic tumor growth and metastasis. In this commentary, we will review these disparate findings and attempt to provide clarity around the role of GREM1 signaling in cancer.

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Conflict of interest statement

Zhichun Gao and Derek P. Brazil have no conflict interest. Peter ten Dijke and Julia Houthuijzen are supported by UCB for research on GREM1 in cancer progression.

Figures

Fig. 1
Fig. 1
Proposed mechanisms of GREM1 signaling in cancer: Bad Cop/Good Cop. A Canonical GREM1 signaling involves GREM1 dimers binding to BMP dimers to prevent BMPR activation and receptor R-SMAD1/5/8 signaling. GREM1 binding to EGFR leads to phosphorylation and activation of STAT3, ERK and AKT in breast cancer cells, facilitating increased invasion (Kim et al. 2020). GREM1 dimer binding to FGFR1 leads to activation of RAS/ERK signaling and in androgen-insensitive prostate cancer cells, driving tumor progression (Lan et al. 2022). GREM1 binding to VEGFR2 has been postulated to drive VEGFR2 activation in endothelial cells, leading to angiogenesis (Mitola et al. 2010). B Increased GREM1 expression from specific subsets of CAFs leads to epithelial-mesenchymal transition and the formation of mesenchymal cancer cells, increased solid tumor formation and tumor cell invasion and metastasis, all of which contribute to poorer patient prognosis in colorectal and other cancers. GREM1 also has an autocrine effect on CAFs, indicated by the curved arrow. Kaplan Meier curve is illustrative of improved survival of patients with low GREM1 mRNA in tumor biopsies (grey line) versus lower survival where GREM1 mRNA are higher (blue line). C Increased methylation of GREM1 promotor regions and reduced GREM1 mRNA were detected in renal cell carcinoma (Morris et al. 2010). D High levels of GREM1 mRNA in stromal fibroblasts from CRC were associated with improved patient survival (Jang et al. 2017). E High GREM1 protein expression in pancreatic NETs correlated with high microvessel density and increased NET differentiation, as well as improved recurrence-free patient survival (Chen et al. 2013). F Grem1 secretion from pancreatic tumor cells that have undergone EMT is proposed to act on pancreatic epithelial cells to inhibit pro-EMT Snail and Slug transcription factor expression and maintain the undifferentiated epithelial cell phenotype in the tumor compartment (Lan et al. 2022). For Panel B and D, Kaplan Meier curves are illustrative of improved survival of patients with high GREM1 mRNA levels in tumor biopsies (grey line) versus lower survival where GREM1 mRNA are lower (blue line). Figures created with BioRender.com
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