Epigenetic control of tissue plasticity in pancreatic regeneration and tumorigenesis.
Cancer results from a complex interaction between genetic mutations and environmental insults that triggers changes in cell identity and tissue state. These changes are highly reminiscent of physiological wound healing processes yet, paradoxically, contribute to cancer development and metastatic progression. To understand how physiological cell and tissue plasticity goes awry during tumor development, we have combined innovative mouse models, functional genomics tools and single-cell assays to define molecular and cellular networks that make the ‘cancer state’ unique. Our work uncovered that the major oncogene in pancreatic cancer (mutant KRAS) hijacks regenerative responses to tissue damage through establishing an aberrant chromatin landscape in pre-neoplastic epithelial cells that reprograms epithelial lineage identity and is necessary for cancer development. We propose that a better understanding of the interplay between genetic mutations, environmental insults and cell identity programs will expose tumor-specific vulnerabilities that may be exploited to improve cancer detection and treatment.