Project description:Metastasis is the cause of death for 90% of cancer patients, but little is known about how cancer cells adapt to and colonize new tissue environments. Using clinical samples and primary/metastatic cell lines, we found metastatic colorectal cancer (CRC) cells lose their colon-specific gene transcription program and gain a liver-specific gene transcription program as they metastasize in the liver. We revealed this transcription reprogramming is driven by a reshaped epigenetic landscape of both typical and super-enhancers. Further, we identified FOXA2, a liver-specific transcription factor, plays a key role in this transcription reprogramming and the colonization of metastatic CRC cells in the liver. Notably, this transcription reprogramming is also observed in multiple cancer types. Our data demonstrate that epigenetically reprogrammed tissue-specific transcription promotes metastasis and should be targeted therapeutically.
Project description:Metastasis is the cause of death for 90% of cancer patients, but little is known about how cancer cells adapt to and colonize new tissue environments. Using clinical samples and primary/metastatic cell lines, we found metastatic colorectal cancer (CRC) cells lose their colon-specific gene transcription program and gain a liver-specific gene transcription program as they metastasize in the liver. We revealed this transcription reprogramming is driven by a reshaped epigenetic landscape of both typical and super-enhancers. Further, we identified FOXA2, a liver-specific transcription factor, plays a key role in this transcription reprogramming and the colonization of metastatic CRC cells in the liver. Notably, this transcription reprogramming is also observed in multiple cancer types. Our data demonstrate that epigenetically reprogrammed tissue-specific transcription promotes metastasis and should be targeted therapeutically.
Project description:Mutations in KRAS, particularly at codon 12, are frequent in adenocarcinomas of the colon, lungs and pancreas, driving carcinogenesis by altering cell signalling and reprogramming metabolism. However, the specific mechanisms by which different KRAS G12 alleles initiate distinctive patterns of metabolic reprogramming are unclear. Using isogenic panels of colorectal cell lines harbouring the G12A, G12C, G12D and G12V heterozygous mutations and employing transcriptomics, metabolomics, and extensive biochemical validation, we characterise distinctive features of each allele. We demonstrate that cells harbouring the common G12D and G12V oncogenic mutations significantly alter glutamine metabolism and nitrogen recycling through FOXO1-mediated regulation compared to parental lines. Moreover, with a combination of small molecule inhibitors targeting glutamine and glutamate metabolism, we also identify a common vulnerability that eliminates mutant cells selectively. These results highlight a previously unreported mutant-specific effect of KRAS alleles on metabolism and signalling that could be potentially harnessed for cancer therapy.