Browsing by Author "Adebayo, Adedeji K."

Now showing 1 - 6 of 6
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    Modeling Preclinical Cancer Studies under Physioxia to Enhance Clinical Translation
    (American Association for Cancer Research, 2022) Adebayo, Adedeji K.; Nakshatri, Harikrishna; Surgery, School of Medicine
    Oxygen (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.
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    Mutant RAS-driven Secretome Causes Skeletal Muscle Defects in Breast Cancer
    (American Association for Cancer Research, 2024) Wang, Ruizhong; Khatpe, Aditi S.; Kumar, Brijesh; Mang, Henry Elmer; Batic, Katie; Adebayo, Adedeji K.; Nakshatri, Harikrishna; Surgery, School of Medicine
    Cancer-induced skeletal muscle defects differ in severity between individuals with the same cancer type. Cancer subtype-specific genomic aberrations are suggested to mediate these differences, but experimental validation studies are very limited. We utilized three different breast cancer patient-derived xenograft (PDX) models to correlate cancer subtype with skeletal muscle defects. PDXs were derived from brain metastasis of triple-negative breast cancer (TNBC), estrogen receptor-positive/progesterone receptor-positive (ER+/PR+) primary breast cancer from a BRCA2-mutation carrier, and pleural effusion from an ER+/PR- breast cancer. While impaired skeletal muscle function as measured through rotarod performance and reduced levels of circulating and/or skeletal muscle miR-486 were common across all three PDXs, only TNBC-derived PDX activated phospho-p38 in skeletal muscle. To further extend these results, we generated transformed variants of human primary breast epithelial cells from healthy donors using HRASG12V or PIK3CAH1047R mutant oncogenes. Mutations in RAS oncogene or its modulators are found in approximately 37% of metastatic breast cancers, which is often associated with skeletal muscle defects. Although cells transformed with both oncogenes generated adenocarcinomas in NSG mice, only HRASG12V-derived tumors caused skeletal muscle defects affecting rotarod performance, skeletal muscle contraction force, and miR-486, Pax7, pAKT, and p53 levels in skeletal muscle. Circulating levels of the chemokine CXCL1 were elevated only in animals with tumors containing HRASG12V mutation. Because RAS pathway aberrations are found in 19% of cancers, evaluating skeletal muscle defects in the context of genomic aberrations in cancers, particularly RAS pathway mutations, may accelerate development of therapeutic modalities to overcome cancer-induced systemic effects. Significance: Mutant RAS- and PIK3CA-driven breast cancers distinctly affect the function of skeletal muscle. Therefore, research and therapeutic targeting of cancer-induced systemic effects need to take aberrant cancer genome into consideration.
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    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 Medicine
    Signaling 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.
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    Oxygen tension-dependent variability in the cancer cell kinome impacts signaling pathways and response to targeted therapies
    (Elsevier, 2024-05-21) Adebayo, Adedeji K.; Bhat-Nakshatri, Poornima; Davis, Christopher; Angus, Steven P.; Erdogan, Cihat; Gao, Hongyu; Green, Nick; Kumar, Brijesh; Liu, Yunlong; Nakshatri, Harikrishna; Surgery, School of Medicine
    Most cells in solid tumors are exposed to oxygen levels between 0.5% and 5%. We developed an approach that allows collection, processing, and evaluation of cancer and non-cancer cells under physioxia, while preventing exposure to ambient air. This aided comparison of baseline and drug-induced changes in signaling pathways under physioxia and ambient oxygen. Using tumor cells from transgenic models of breast cancer and cells from breast tissues of clinically breast cancer-free women, we demonstrate oxygen-dependent differences in cell preference for epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor beta (PDGFRβ) signaling. Physioxia caused PDGFRβ-mediated activation of AKT and extracellular regulated kinase (ERK) that reduced sensitivity to EGFR and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) inhibition and maintained PDGFRβ+ epithelial-mesenchymal hybrid cells with potential cancer stem cell (CSC) properties. Cells in ambient air displayed differential EGFR activation and were more sensitive to targeted therapies. Our data emphasize the importance of oxygen considerations in preclinical cancer research to identify effective drug targets and develop combination therapy regimens.
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    Single-nucleus chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry
    (Springer Nature, 2024) Bhat-Nakshatri, Poornima; Gao, Hongyu; Khatpe, Aditi S.; Adebayo, Adedeji K.; McGuire, Patrick C.; Erdogan, Cihat; Chen, Duojiao; Jiang, Guanglong; New, Felicia; German, Rana; Emmert, Lydia; Sandusky, George; Storniolo, Anna Maria; Liu, Yunlong; Nakshatri, Harikrishna; Surgery, School of Medicine
    Single-nucleus analysis allows robust cell-type classification and helps to establish relationships between chromatin accessibility and cell-type-specific gene expression. Here, using samples from 92 women of several genetic ancestries, we developed a comprehensive chromatin accessibility and gene expression atlas of the breast tissue. Integrated analysis revealed ten distinct cell types, including three major epithelial subtypes (luminal hormone sensing, luminal adaptive secretory precursor (LASP) and basal-myoepithelial), two endothelial and adipocyte subtypes, fibroblasts, T cells, and macrophages. In addition to the known cell identity genes FOXA1 (luminal hormone sensing), EHF and ELF5 (LASP), TP63 and KRT14 (basal-myoepithelial), epithelial subtypes displayed several uncharacterized markers and inferred gene regulatory networks. By integrating breast epithelial cell gene expression signatures with spatial transcriptomics, we identified gene expression and signaling differences between lobular and ductal epithelial cells and age-associated changes in signaling networks. LASP cells and fibroblasts showed genetic ancestry-dependent variability. An estrogen receptor-positive subpopulation of LASP cells with alveolar progenitor cell state was enriched in women of Indigenous American ancestry. Fibroblasts from breast tissues of women of African and European ancestry clustered differently, with accompanying gene expression differences. Collectively, these data provide a vital resource for further exploring genetic ancestry-dependent variability in healthy breast biology.
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    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 Medicine
    Preclinical 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.