KDM8 is a master regulator for hypoxia-induced metastatic heterogeneity in pancreatic cancer [scRNA-Seq]

This study aims to elucidate how hypoxia promotes pancreatic cancer metastasis by suppressing the JmjC-containing histone lysine demethylase KDM8. In solid tumors, hypoxia is a key factor that reprograms cancer cells into a highly metastatic state. Hypoxia is a well-established inducer of epithelial-to-mesenchymal transition, which is associated with treatment resistance and metastasis. In addition, hypoxia promotes chromosomal instability - a hallmark of cancer and a key contributor to metastasis. Despite this, the mechanisms by which cancer cells simultaneously hijack these elements of hypoxic adaptation to promote metastasis remains unknown. We found that CRISPR-mediated targeting of Kdm8 in a genetically engineered mouse model of pancreatic ductal adenocarcinoma rewires the cancer cell transcriptomic programs, leading to a profound loss of the differentiated morphology and widespread metastatic disease. Importantly, Kdm8 suppression in normoxia recapitulates major aspects of the global epigenetic changes and the transcriptomic rewiring induced by hypoxia. Further, Kdm8 deficiency leads to mitotic defects, increased micronuclei formation, Kras copy number gains, and enhanced chromosomal instability. Notably, disruption of the demethylase function of KDM8 phenocopies the effects of KDM8 loss, whereas expression of hypermorphic KDM8 variants that are resistant to hypoxic suppression reduces metastasis beyond that achieved by the wildtype Kdm8. Through the suppression of Kdm8 demethylase activity, hypoxia unleashes a potent metastatic program by simultaneously advancing cellular plasticity and chromosomal instability.