Hypoxia-induced metastatic heterogeneity in pancreatic cancer

In most solid tumors, hypoxia is a critical physical attribute that reprograms malignant cells into a highly metastatic state. Specifically, hypoxia is a well-established inducer of cellular plasticity, which is associated with treatment resistance and metastasis. Furthermore, hypoxia exacerbates chromosomal instability (CIN), a hallmark of cancer that can be initiated by the loss of Trp53 and a key contributor to metastasis. Despite this, the mechanisms by which malignant cells concurrently co-opt these elements of hypoxic adaptation to promote metastasis remains unknown. Here we report that hypoxia promotes metastasis by suppressing the JmjC-containing histone lysine demethylase Kdm8. CRISPR/Cas9-mediated targeting of Kdm8 in a Kras;Trp53-driven mouse model of pancreatic ductal adenocarcinoma robustly rewires the malignant cell transcriptomic programs, leading to a profound loss of the epithelial morphology and widespread metastatic disease. Mechanistically, Kdm8 suppression in normoxia recapitulates major aspects of the global epigenetic changes and the transcriptomic rewiring induced by hypoxia. Moreover, Kdm8 deficiency leads to mitotic defects, increased micronuclei formation, Kras copy number gains, and enhanced CIN. Of note, disruption of Kdm8's demethylase function phenocopies the effects of Kdm8 loss, whereas expression of hypermorphic Kdm8 variants that are resistant to hypoxic suppression reduces metastasis beyond the levels achieved by the wildtype counterpart. Through the suppression of Kdm8 demethylase activity, hypoxia unleashes a potent metastatic program by simultaneously advancing cellular plasticity and CIN.