The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Salvador-Barbero, B. et al. Gastroenterology. (2025).
doi: 10.1053/j.gastro.2025.02.042.
Summary of the findings
Summary of the findingsPancreatic cancer arises from cells carrying genetic mutations in oncogenic KRAS. We discovered that the pancreas protects against disease by actively eliminating KrasG12D-expressing cells. This suggests that for cancer to start, KrasG12D cells must override cell elimination mechanisms to survive in tissues. However, what controls whether mutant cells are eliminated or survive has remained unclear.
Here, we found that not all KrasG12D cells are eliminated from the pancreas, suggesting some cells have a survival advantage. We discovered that surviving cells switch on genes that regulate cell dormancy, stem and progenitor cell fates and non-canonical Wnt signalling in vivo. Using RAS-normal coculture assays, we showed that Wnt5a increases E-cadherin-based cell-cell adhesions at normal-mutant cell-cell boundaries, allowing RAS cells to stay in the epithelium. This is reversed upon WNT inhibition, suggesting WNT signalling is required to keep RAS cells attached to normal neighbours and prevent mutant cell expulsion. We showed that WNT signalling is active, and E-cadherin-based cell-cell adhesions are increased at mutant-normal cell boundaries in vivo. Inhibition of WNT in vivo caused a loss of KrasG12D cells from the pancreas. In addition, human data revealed increased WNT5A expression in pancreatic cancer precursor lesions. Thus, WNT5A signalling is required to promote E-cadherin-based cell-cell adhesion between mutant cells and normal neighbours, boosting mutant cell survival.
Our data show that genetic mutations alone are insufficient to induce cancer and suggest that when present in adult tissues in low numbers, cell survival is an essential first step. Future work will unravel the additional cues mutant cells need to avoid tissue defence mechanisms and progress from a dormant-like state to precancerous lesions. A better understanding of these very early stages is critical for the development of early detection and prevention cancer strategies.
