Clinical molecular subtyping reveals intrinsic mesenchymal reprogramming in gastric cancer cells

The mesenchymal cancer phenotype is known to be clinically related to treatment resistance and a poor prognosis. We identified gene signature-based molecular subtypes of gastric cancer (GC, n = 547) based on transcriptome data and validated their prognostic and predictive utility in multiple external cohorts. We subsequently examined their associations with tumor microenvironment (TME) features by employing cellular deconvolution methods and sequencing isolated GC populations. We further performed spatial transcriptomics analysis and immunohistochemistry, demonstrating the presence of GC cells in a partial epithelial-mesenchymal transition state. We performed network and pharmacogenomic database analyses to identify TGF-β signaling as a driver pathway and, thus, a therapeutic target. We further validated its expression in tumor cells in preclinical models and a single-cell dataset. Finally, we demonstrated that inhibition of TGF-β signaling negated mesenchymal/stem-like behavior and therapy resistance in GC cell lines and mouse xenograft models. In summary, we show that the mesenchymal GC phenotype could be driven by epithelial cancer cell-intrinsic TGF-β signaling and propose therapeutic strategies based on targeting the tumor-intrinsic mesenchymal reprogramming of medically intractable GC. Targeting a growth factor protein could reprogram tumor cells in difficult-to-treat gastric cancer, improving chemotherapy responses and prognosis. Several subtypes of gastric cancer are intractable and chemo-resistant. These often display elevated levels of genes expressed in mesenchymal stem cells, multipotent cells that are frequently involved in cancer progression. Jae-Ho Cheong and Yong-Min Huh at Yonsei University, Seoul, South Korea, and co-workers used gene expression profiling on samples from 547 patients to clarify gastric cancer molecular subtypes and their associated gene signatures. They validated their results against multiple external patient groups, and examined the association betweenf different subtypes and the tumour microenvironment. Experiments on mouse models showed that the transforming growth factor-beta pathway (TGF-β) drives the switch from normal to mesenchymal stem cell state of cancer cells not stormal cells. Inhibiting TGF-β signaling in gastric cancer cells blocked this transition and reduced chemotherapy resistance. Introduction