Autophagy drives compartment‐specific oncogenesis: HIF1‐alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells

Our recent studies have mechanistically implicated HIF1‐alpha activation in driving the cancer‐associated fibroblast phenotype, through the paracrine production of nutrients via autophagy and aerobic glycolysis. To test this hypothesis directly, we stably‐expressed activated HIF1a in fibroblasts and then examined their ability to promote tumor growth using a xenograft model employing human breast cancer cells (MDA‐MB‐231). Fibroblasts harboring activated HIF1a showed a shift towards aerobic glycolysis, as evidenced by a loss of mitochondrial activity, and an increase in lactate production. Importantly, fibroblasts expressing activated HIF1a increased tumor mass by 2‐fold and tumor volume by 3‐fold, without a significant increase in tumor angiogenesis. It is also known that HIF1a expression is required for the induction of autophagy in cancer cells. As such, we next directly expressed activated HIF1a in MDA‐MB‐231 cells and assessed its effect on tumor growth via xenograft analysis.Surprisingly, activated HIF1a in cancer cells dramatically suppressed tumor growth, resulting in a 2‐fold reduction in tumor mass and a 3‐fold reduction in tumor volume. We conclude that HIF1a activation in different cell types can either promote or repress tumorigenesis.