A Mechanistic Model of the HIF-1/HIF-2 Switch Regulating Hypoxia-Induced Cancer Stemness

A common hypoxic scenario in tumors involves unresolved acute hypoxia that eventually leads to sustained (chronic) hypoxia. This shift drives a characteristic "HIF switch", where the key hypoxia-responsive factors change from HIF-1α to HIF-2α over time, and importantly, this switch is closely linked to stemness regulation. However, the mechanisms underlying this switch and its impact on stemness regulation are not yet fully understood. Here, we developed a mechanistic network model integrating the HIF-1/HIF-2 signaling axis with the stemness regulators OCT4 and SOX2. We found that the duration and intensity of hypoxia jointly shape the dynamics of HIF-1α and HIF-2α, ultimately regulating OCT4-mediated stemness. Under physioxia, HIF-2α-mTORC2 positive feedback supports the gradual accumulation of HIF-2α toward a modest steady level and low OCT4 expression, corresponding to a primed state. Under prolonged mild hypoxia, the concurrent induction of HIF-1α, albeit at low levels, and accelerated accumulation of HIF-2α elevate OCT4 to intermediate levels, promoting stem-like traits. Under moderate hypoxia, PHD-2-mediated negative feedback triggers pulsatile HIF-1α dynamics, driving a shift toward HIF-2α dominance. Ultimately, cooperative HIF-1α/HIF-2α signaling induces REDD1 and suppresses mTORC1-dependent protein synthesis, pushing OCT4 into a high-expression state associated with differentiation. This work presents a unified framework for understanding how the HIF signaling hierarchy coordinates metabolic and transcriptional programs to direct cell fate across varying hypoxic landscapes.