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Tumor collection/processing under physioxia uncovers highly relevant signaling networks and drug sensitivity.

ABSTRACT: 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.

SUBMITTER: Kumar B

PROVIDER: S-EPMC8754301 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Tumor collection/processing under physioxia uncovers highly relevant signaling networks and drug sensitivity.

Kumar Brijesh B Adebayo Adedeji K AK Prasad Mayuri M Capitano Maegan L ML Wang Ruizhong R Bhat-Nakshatri Poornima P Anjanappa Manjushree M Simpson Edward E Chen Duojiao D Liu Yunlong Y Schilder Jeanne M JM Colter Austyn B AB Maguire Callista C Temm Constance J CJ Sandusky George G Doud Emma H EH Wijeratne Aruna B AB Mosley Amber L AL Broxmeyer Hal E HE Nakshatri Harikrishna H

Science advances 20220112 2

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 ambi ...[more]

PMID: 35020422

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Project description:Preclinical studies of primary cancer cells are always done after tumors are removed from patients or animals at ambient atmospheric oxygen (O2, ~21%). However, O2 concentrations in organs are in the ~3-10% range, with most tumors in an hypoxic or 1-2% 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 anti-cancer agents is routinely examined at ambient O2. Here, using both mouse models and human cancers, we demonstrate that tumors collected, processed and propagated at physiologic (physioxia) O2 compared to ambient air display very distinct differences in key signaling networks including Lgr5/Wnt, Yap, and Nrf2/Keap1, nuclear reactive oxygen species levels, alternative splicing, and sensitivity to several targeted therapies including PIK3CAalpha-specific and EGFR inhibitors. Significance: Extra-physiologic oxygen shock/stress (EPHOSS), as noted in cells collected/processed under ambient air, has been demonstrated to have significant impact on numbers and engrafting ability of hematopoietic stem cells. We report deleterious effects of EPHOSS on cancer cell behavior and EPHOSS-mediated effects on cancer cells give misleading information on signaling pathway activation that could severely impact the relevance of these findings. Cancer cells under EPHOSS show higher proliferation rate compared to cells under physioxia and thus are sensitive to anti-proliferative agents. Thus, drugs that show effectiveness on cancer cells collected in ambient air and subjected to EPHOSS may not be effective or as relevant in vivo, results that could partially explain the limited clinical translation of laboratory findings. Evaluating cell signaling and effects of drugs on cancer cells under physiologic O2 prior to in vivo studies could substantially reduce cost and aid in drug discovery relevant to the actual physioxia/pathological status of the tumor cells in vivo.

Project description:The need for fast and dynamic processing of relevant information imposes high demands onto the flexibility and efficiency of the nervous system. A good example for such flexibility is the attention-dependent selection of relevant sensory information. Studies investigating attentional modulations of neuronal responses to simultaneously arriving input showed that neurons respond, as if only the attended stimulus would be present within their receptive fields (RF). However, attention also improves neuronal representation and behavioral performance, when only one stimulus is present. Thus, attention serves for selecting relevant input and changes the neuronal processing of signals representing selected stimuli, ultimately leading to a more efficient behavioral performance. Here, we tested the hypothesis that attention configures the strength of functional coupling between a local neuronal network's neurons specifically for effective processing of signals representing attended stimuli. This coupling is measured as the strength of γ-synchronization between these neurons. The hypothesis predicts that the pattern of synchronization in local networks should depend on which stimulus is attended. Furthermore, we expect this pattern to be similar for the attended stimulus presented alone or together with irrelevant stimuli in the RF. To test these predictions, we recorded spiking-activity and local field potentials (LFP) with closely spaced electrodes in area V4 of monkeys performing a demanding attention task. Our results show that the γ-band phase coherence (γ-PhC) between spiking-activity and the LFP, as well as the spiking-activity of two groups of neurons, strongly depended on which of the two stimuli in the RF was attended. The γ-PhC was almost identical for the attended stimulus presented either alone or together with a distractor. The functional relevance of dynamic γ-band synchronization is further supported by the observation of strongly degraded γ-PhC before behavioral errors, while firing rates were barely affected. These qualitatively different results point toward a failure of attention-dependent top-down mechanisms to correctly synchronize the local neuronal network in V4, even though this network receives the correctly selected input. These findings support the idea of a flexible, demand-dependent dynamic configuration of local neuronal networks, for performing different functions, even on the same sensory input.

Dataset Information

Tumor collection/processing under physioxia uncovers highly relevant signaling networks and drug sensitivity.

Publications

Tumor collection/processing under physioxia uncovers highly relevant signaling networks and drug sensitivity.

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