Intratumoral hypoxia is one of the most important factors present in the tumor microenvironment, regulating various steps in cancer growth and metastasis, including metabolism, vascularization, premetastatic niche formation, and dormancy. Cellular response to hypoxia is highly regulated, and is mediated by hypoxia-inducible factors (HIF), consisting of an oxygen (O2) regulated subunit, among which HIF-1α is the ubiquitously expressed homologue. HIF-1α stabilizes in hypoxia, and transcriptionally activates more than 1500 HIF identified target genes. Changes in HIF-1α activity, can, therefore result in large changes in gene expression, and phenotypic state of the cells. However, there are paradoxes in observations of HIF-1α responses. HIF-1α inhibits cell proliferation, but cells continue to divide in hypoxia. Similarly, HIF-1α induced indirect phosphorylation and inhibition of pyruvate dehydrogenase (PDH) diverts pyruvate away from acetyl-CoA toward lactate synthesis, decreasing respiration; but HIF-1α can also enhance mitochondrial respiration efficiency by controlling the expression cytochrome c oxidase type 4 (COX4) subunits. These paradoxes could potentially be addressed if individual cellular responses to hypoxia may be different than the bulk/average cell responses.Using fluorescent dynamic reporters of HIF-1α activity, we show that hypoxic responses in individual cells can be highly dynamic and variable across the population. These responses fall into three classes, including oscillatory activity. We identify a molecular mechanism that can account for all three response classes, demonstrating that the oscillations of HIF-1a activity and abundance are controlled by the reactive oxygen species-dependent chaperone-mediated autophagy in a subset of respiring cells. Furthermore, we find that the oscillatory response is modulated by the abundance of extracellular lactate in a quorum sensing-like mechanism. Importantly, we demonstrate that oscillatory HIF-1α activity promotes differential gene expression leading to enhanced cell division, which can help reduce the anti-proliferative effect of hypoxia. These results may help resolve the paradox of seemingly contradicting roles of HIF-1α in the control of metabolic cell states and cell proliferation. Further, specific transcription by oscillatory hypoxia suggest that gene regulation can specifically decode oscillatory signals, resulting in novel phenotypes in a subpopulation, with a selective advantage to survive and proliferate under hypoxic stress.

Note: This abstract was not presented at the meeting.

Citation Format: Kshitiz ., Junaid Afzal, Yasir Suhail, Hao Chang, Chi V. Dang, Andre Levchenko. Oscillatory HIF-1α induction promotes proliferation of hypoxic cells through a lactate dependent quorum autophagy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4359.