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Browsing by Author "Adebayo, Adedeji K."
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Item Modeling Preclinical Cancer Studies under Physioxia to Enhance Clinical Translation(American Association for Cancer Research, 2022) Adebayo, Adedeji K.; Nakshatri, Harikrishna; Surgery, School of MedicineOxygen (O2) plays a key role in cellular homeostasis. O2 levels are tightly regulated in vivo such that each tissue receives an optimal amount to maintain physiologic status. Physiologic O2 levels in various organs range between 2–9% in vivo, with the highest levels of 9% in the kidneys and the lowest of 0.5% in parts of the brain. This physiologic range of O2 tensions is disrupted in pathologic conditions such as cancer, where it can reach as low as 0.5%. Regardless of the state, O2 tension in vivo is maintained at significantly lower levels than ambient O2, which is approximately 21%. Yet, routine in vitro cellular manipulations are carried out in ambient air, regardless of whether or not they are eventually transferred to hypoxic conditions for subsequent studies. Even brief exposure of hematopoietic stem cells to ambient air can cause detrimental effects through a mechanism termed extraphysiologic oxygen shock/stress (EPHOSS), leading to reduced engraftment capabilities. Here, we provide an overview of the effects of ambient air exposure on stem and non-stem cell subtypes, with a focus on recent findings that reveal the impact of EPHOSS on cancer cells.Item Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer(MDPI, 2021-01-20) Khatpe, Aditi S.; Adebayo, Adedeji K.; Herodotou, Christopher A.; Kumar, Brijesh; Nakshatri, Harikrishna; Surgery, School of MedicineSignaling from estrogen receptor alpha (ERα) and its ligand estradiol (E2) is critical for growth of ≈70% of breast cancers. Therefore, several drugs that inhibit ERα functions have been in clinical use for decades and new classes of anti-estrogens are continuously being developed. Although a significant number of ERα+ breast cancers respond to anti-estrogen therapy, ≈30% of these breast cancers recur, sometimes even after 20 years of initial diagnosis. Mechanism of resistance to anti-estrogens is one of the intensely studied disciplines in breast cancer. Several mechanisms have been proposed including mutations in ESR1, crosstalk between growth factor and ERα signaling, and interplay between cell cycle machinery and ERα signaling. ESR1 mutations as well as crosstalk with other signaling networks lead to ligand independent activation of ERα thus rendering anti-estrogens ineffective, particularly when treatment involved anti-estrogens that do not degrade ERα. As a result of these studies, several therapies that combine anti-estrogens that degrade ERα with PI3K/AKT/mTOR inhibitors targeting growth factor signaling or CDK4/6 inhibitors targeting cell cycle machinery are used clinically to treat recurrent ERα+ breast cancers. In this review, we discuss the nexus between ERα-PI3K/AKT/mTOR pathways and how understanding of this nexus has helped to develop combination therapies.Item Tumor collection/processing under physioxia uncovers highly relevant signaling networks and drug sensitivity(American Association for the Advancement of Science, 2022) Kumar, Brijesh; Adebayo, Adedeji K.; Prasad, Mayuri; Capitano, Maegan L.; Wang, Ruizhong; Bhat-Nakshatri, Poornima; Anjanappa, Manjushre; Simpson, Edward; Chen, Duojiao; Liu, Yunlong; Schilder, Jeanne M.; Colter, Austyn B.; Maguire, Callista; Temm, Constance J.; Sandusky, George; Doud, Emma H.; Wijeratne, Aruna B.; Mosley, Amber L.; Broxmeyer, Hal E.; Nakshatri, Harikrishna; Microbiology and Immunology, School of MedicinePreclinical studies of primary cancer cells are typically done after tumors are removed from patients or animals at ambient atmospheric oxygen (O2, ~21%). However, O2 concentrations in organs are in the ~3 to 10% range, with most tumors in a hypoxic or 1 to 2% O2 environment in vivo. Although effects of O2 tension on tumor cell characteristics in vitro have been studied, these studies are done only after tumors are first collected and processed in ambient air. Similarly, sensitivity of primary cancer cells to anticancer agents is routinely examined at ambient O2. Here, we demonstrate that tumors collected, processed, and propagated at physiologic O2 compared to ambient air display distinct differences in key signaling networks including LGR5/WNT, YAP, and NRF2/KEAP1, nuclear reactive oxygen species, alternative splicing, and sensitivity to targeted therapies. Therefore, evaluating cancer cells under physioxia could more closely recapitulate their physiopathologic status in the in vivo microenvironment.