Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous cancer with limited understanding of its classification and tumor microenvironment. Here, by analyzing single-nucleus RNA sequencing of 43, 817 tumor cells from 15 PDAC tumors and non-tumor, we find that hypoxia signatures were heterogeneous across samples and were potential regulators for tumor progression and more aggressive phenotype. Hypoxia-high PDAC tends to present a basal/squamous-like phenotype and has significantly increased outgoing signaling, which enhances tumor cell stemness and promotes metastasis, angiogenesis, and fibroblast differentiation in PDAC. Hypoxia is related to an extracellular matrix enriched microenvironment, and increased possibility of TP53 mutation in PDAC. TP63 is a specific marker of squamous-like phenotype, and presents elevated transcriptome levels in most hypoxia PDAC tumors. In summary, our research highlights the potential linkage of hypoxia, tumor progression and genome alteration in PDAC, leading to further understand of the formation of inter-tumoral and intra-tumoral heterogenous in PDAC. Our study extends the understanding of the diversity and transition of tumor cells in PDAC, which provides insight into future PDAC management.