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Cancer Res. 2019 Oct 4. pii: canres.2994.2018. doi: 10.1158/0008-5472.CAN-18-2994. [Epub ahead of print]

Absence of HIF1A leads to glycogen accumulation and an inflammatory response that enables pancreatic tumor growth.

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Cancer Center, Sanford Burnham Prebys Medical Discovery Institute.
Cancer Vaccines Immunotherapeutics, Pfizer, Inc.
Sanford-Burnham Medical Discovery Institute.
Histology, Sanford-Burnham Medical Discovery Institute.
Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute.
Translational Development, Celgene (United States).
Pharmacology and Toxicology, University of Utah.
Sanford-Burnham Medical Discovery Institute


Cancer cells respond to hypoxia by upregulating the hypoxia-inducible factor 1α HIF1A) transcription factor, which drives survival mechanisms that include metabolic adaptation and induction of angiogenesis by vascular endothelial growth factor (VEGF). Pancreatic tumors are poorly vascularized and severely hypoxic. To study the angiogenic role of HIF1A, and specifically probe whether tumors are able to use alternative pathways in its absence, we created a xenograft mouse tumor model of pancreatic cancer lacking HIF1A. After an initial delay of about 30 days the HIF1A-deficient tumors grew as rapidly as the wild type tumors and had similar vascularization. These changes were maintained in subsequent passages of tumor xenografts in vivo and in cell lines ex vivo. There were many cancer cells with a "clear cell" phenotype in the HIF1A-deficient tumors; this was the result of accumulation of glycogen. Single-cell RNA sequencing (scRNAseq) of the tumors identified hypoxic cancer cells with inhibited glycogen breakdown which promoted glycogen accumulation, and the secretion of inflammatory cytokines including interleukins 1β (IL-1B) and 8 (IL-8). scRNAseq of the mouse tumor stroma showed enrichment of 2 subsets of myeloid dendritic cells (cDC), cDC1 and cDC2, that secreted pro-angiogenic cytokines. These results suggest that glycogen accumulation associated with a clear cell phenotype in hypoxic cancer cells lacking HIF1A can initiate an alternate pathway of cytokine and DC-driven angiogenesis. Inhibiting glycogen accumulation may provide a treatment for cancers with the clear cell phenotype.

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