Reprogramming of cellular energy metabolism is widely accepted to be one of the main hallmarks of cancer. The aberrant expression pattern of key regulators in the glycolysis pathway in cancer cells ...corroborates with the hypothesis that most cancer cells utilize aerobic glycolysis as their main ATP production method instead of mitochondrial oxidative phosphorylation. Overexpression of SLC2A1 and LDHA, both important regulators of the glycolysis pathway, was detected in the premalignant lesions and tumors of lung cancer patients, suggesting the involvement of these proteins in early carcinogenesis and tumor progression in cancer. Preclinical studies demonstrated that inhibiting SLC2A1 or LDHA led to diminished tumor growth in vitro and in vivo. SLC2A1 and LDHA inhibitors, when administered in combination with other chemotherapeutic agents, showed synergistic antitumor effects by resensitizing chemoresistant cancer cells to the chemotherapies. These results indicate that disrupting SLC2A1, LDHA, or other regulators in cancer cell energetics is a very promising approach for new targeted therapies.
Respiratory diseases are a major reason for death in both men and women worldwide. The development of therapies for these diseases has been slow and the lack of relevant human models to understand ...lung biology inhibits therapeutic discovery. The lungs are structurally and functionally complex with many different cell types which makes designing relevant lung models particularly challenging. The traditional two-dimensional (2D) cell line cultures are, therefore, not a very accurate representation of the in vivo lung tissue. The recent development of three-dimensional (3D) co-culture systems, popularly known as organoids/spheroids, aims to bridge the gap between 'in-dish' and 'in-tissue' cell behavior. These 3D cultures are modeling systems that are widely divergent in terms of culturing techniques (bottom-up/top-down) that can be developed from stem cells (adult/embryonic/pluripotent stem cells), primary cells or from two or more types of cells, to build a co-culture system. Lung 3D models have diverse applications including the understanding of lung development, lung regeneration, disease modeling, compound screening, and personalized medicine. In this review, we discuss the different techniques currently being used to generate 3D models and their associated cellular and biological materials. We further detail the potential applications of lung 3D cultures for disease modeling and advances in throughput for drug screening.
Viruses hijack host cell metabolism to acquire the building blocks required for replication. Understanding how SARS-CoV-2 alters host cell metabolism may lead to potential treatments for COVID-19. ...Here we profile metabolic changes conferred by SARS-CoV-2 infection in kidney epithelial cells and lung air-liquid interface (ALI) cultures, and show that SARS-CoV-2 infection increases glucose carbon entry into the TCA cycle via increased pyruvate carboxylase expression. SARS-CoV-2 also reduces oxidative glutamine metabolism while maintaining reductive carboxylation. Consistent with these changes, SARS-CoV-2 infection increases the activity of mTORC1 in cell lines and lung ALI cultures. Lastly, we show evidence of mTORC1 activation in COVID-19 patient lung tissue, and that mTORC1 inhibitors reduce viral replication in kidney epithelial cells and lung ALI cultures. Our results suggest that targeting mTORC1 may be a feasible treatment strategy for COVID-19 patients, although further studies are required to determine the mechanism of inhibition and potential efficacy in patients.
Airways are exposed to myriad environmental and damaging agents such as reactive oxygen species (ROS), which also have physiological roles as signaling molecules that regulate stem cell function. ...However, the functional significance of both steady and dynamically changing ROS levels in different stem cell populations, as well as downstream mechanisms that integrate ROS sensing into decisions regarding stem cell homeostasis, are unclear. Here, we show in mouse and human airway basal stem cells (ABSCs) that intracellular flux from low to moderate ROS levels is required for stem cell self-renewal and proliferation. Changing ROS levels activate Nrf2, which activates the Notch pathway to stimulate ABSC self-renewal and an antioxidant program that scavenges intracellular ROS, returning overall ROS levels to a low state to maintain homeostatic balance. This redox-mediated regulation of lung stem cell function has significant implications for stem cell biology, repair of lung injuries, and diseases such as cancer.
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•ROS level flux regulates self-renewal of mouse and human airway basal stem cells•ROS flux signals through Nrf2 to regulate the canonical Notch pathway•Notch regulates airway basal stem cell self-renewal•Control of ROS flux by Nrf2 is critical for preserving airway stem cell homeostasis
Paul et al. show that dynamic changes in the levels of reactive oxygen species activate Notch signaling to control proliferation and self-renewal of airway basal stem cells.
The respiratory tract is a vital, intricate system for several important biological processes including mucociliary clearance, airway conductance, and gas exchange. The Wnt signaling pathway plays ...several crucial and indispensable roles across lung biology in multiple contexts. This review highlights the progress made in characterizing the role of Wnt signaling across several disciplines in lung biology, including development, homeostasis, regeneration following injury, in vitro directed differentiation efforts, and disease progression. We further note uncharted directions in the field that may illuminate important biology. The discoveries made collectively advance our understanding of Wnt signaling in lung biology and have the potential to inform therapeutic advancements for lung diseases.
Small-cell neuroendocrine cancers (SCNCs) are an aggressive cancer subtype. Transdifferentiation toward an SCN phenotype has been reported as a resistance route in response to targeted therapies. ...Here, we identified a convergence to an SCN state that is widespread across epithelial cancers and is associated with poor prognosis. More broadly, non-SCN metastases have higher expression of SCN-associated transcription factors than non-SCN primary tumors. Drug sensitivity and gene dependency screens demonstrate that these convergent SCNCs have shared vulnerabilities. These common vulnerabilities are found across unannotated SCN-like epithelial cases, small-round-blue cell tumors, and unexpectedly in hematological malignancies. The SCN convergent phenotype and common sensitivity profiles with hematological cancers can guide treatment options beyond tissue-specific targeted therapies.
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•Pan-tissue convergent molecular programs in small-cell neuroendocrine (SCN) cancers•Poorer prognosis for tumors with high SCN signatures across epithelial cancers•Drug sensitivity profiles are shared between SCN cancers and blood cancers•SCN cancers and hematological malignancies have common functional dependencies
Balanis, Sheu, et al. identify a small-cell neuroendocrine (SCN) state across various epithelial cancer types that shares genome-wide expression, methylation, and copy-number alteration patterns and associates with poor prognosis. SCN cancers have common vulnerabilities that, unexpectedly, are shared with blood cancers.
Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Although infection initiates in the proximal ...airways, severe and sometimes fatal symptoms of the disease are caused by infection of the alveolar type 2 (AT2) cells of the distal lung and associated inflammation. In this study, we develop primary human lung epithelial infection models to understand initial responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface (ALI) cultures of proximal airway epithelium and alveosphere cultures of distal lung AT2 cells are readily infected by SARS-CoV-2, leading to an epithelial cell-autonomous proinflammatory response with increased expression of interferon signaling genes. Studies to validate the efficacy of selected candidate COVID-19 drugs confirm that remdesivir strongly suppresses viral infection/replication. We provide a relevant platform for study of COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and emergent respiratory pathogens.
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•Human alveospheres are composed of renewing AT2 cells and AT1-like cells•Alveolar epithelial cells are efficiently infected by SARS-CoV-2 in vitro•Interferon signaling is activated in SARS-CoV-2-infected alveolar epithelial cells•Lung organoid models provide a platform for drug discovery and disease modeling
In vitro models of human lung epithelium, including diverse cell types of the proximo-distal axis, are critical for modeling infection. Mulay et al. show that alveospheres, with epithelial type 2- and type 1-like cells, are infected by SARS-CoV-2, initiating an interferon response, and serve as a platform for screening antiviral drugs.
The role of CXC chemokines in pulmonary fibrosis Strieter, Robert M; Gomperts, Brigitte N; Keane, Michael P
The Journal of clinical investigation,
03/2007, Volume:
117, Issue:
3
Journal Article
Peer reviewed
Open access
The CXC chemokine family is a pleiotropic family of cytokines that are involved in promoting the trafficking of various leukocytes, in regulating angiogenesis and vascular remodeling, and in ...promoting the mobilization and trafficking of mesenchymal progenitor cells such as fibrocytes. These functions of CXC chemokines are important in the pathogenesis of pulmonary fibrosis and other fibroproliferative disorders. In this Review, we discuss the biology of CXC chemokine family members, specifically as it relates to their role in regulating vascular remodeling and trafficking of circulating mesenchymal progenitor cells (also known as fibrocytes) in pulmonary fibrosis.
Fibrocytes in lung disease Gomperts, Brigitte N.; Strieter, Robert M.
Journal of leukocyte biology,
September 2007, Volume:
82, Issue:
3
Journal Article
Peer reviewed
Open access
Fibrocytes were first described over a decade ago as a population of cells in circulation with fibroblast‐like properties, which were involved in tissue repair. Since that time, we have learned a ...significant amount about these bone marrow‐derived cells, which contribute to wound healing and fibrosis. Fibrocytes express leukocyte markers such as CD34, CD45, and CD13 and also express mesenchymal markers such as pro‐collagens I and III, vimentin, and fibronectin. In addition, they have been shown to express the chemokine receptors CXCR4 and CCR7, which appear to be important in cellular trafficking from the vascular to the extravascular compartment. Fibrocytes have been shown to contribute to a number of fibrotic disorders, and here, we review their involvement in lung diseases including pulmonary fibrosis, asthma, and vascular remodeling.
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