GREM1 Restricts Plasticity and Maintains Heterogeneity in Pancreatic Cancer

Cellular heterogeneity is a prominent clinical feature of pancreatic ductal adenocarcinoma (PDAC). Within PDAC, there are distinct epithelial and mesenchymal tumor cell populations, but how these populations are established and interact with with one another has not been well defined. Lan and colleagues analyzed gene expression data from a genetically engineered mouse model (GEMM) and human PDACs and found that the secreted factor gene Grem1 is specifically upregulated within the mesenchymal pancreatic tumor cell population. In order to understand the functional role of GREM1, the authors developed a sequential recombination mouse model in which they deleted Grem1 in established murine PDAC tumors. Although there was no notable change in survival, Grem1 knockout caused a significant change in histology, forcing tumors from a typical epithelial, duct-like state into a predominantly mesenchymal, spindle-like state. This rapid epithelial-to-mesenchymal shift following Grem1 deletion was also associated with an increase in the rate of metastasis. Overexpression of Grem1 in GEMM-derived organoids increased the expression of epithelial markers and suppressed mesenchymal and epithelial-to-mesenchymal transition (EMT) genes. Additionally, Grem1 overexpression reverted the mesenchymal features of human PDAC cells, suggesting that secreted GREM1 is capable of both blocking and reversing EMT. Because GREM1 is a known BMP signaling antagonist, the authors investigated this pathway in the epithelial and mesenchymal populations. Interestingly, mesenchymal cells showed high levels of BMP pathway activity despite expression of Grem1. Chromatin immunoprecipitation analysis revealed that the downstream effectors of BMP signaling, phosphorylated SMAD1/5/9, were bound to the promoter region of Grem1, pointing to a negative feedback mechanism, whereas in epithelial cells with low BMP levels GREM1 inhibition of BMP signaling prevented the activation of EMT transcriptional machinery. Altogether, these data show that GREM1 secreted from mesenchymal tumor cells is critical for the maintenance of cellular heterogeneity by reinforcing epithelial identity via canonical BMP signaling.

Lan L, Evan T, Li H, Hussain A, Ruiz EJ, Thin MZ, et al. GREM1 is required to maintain cellular heterogeneity in pancreatic cancer. Nature 2022;607:163–8.

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