Biology subjects

Wallace, W. D.

Publications and source records attributed to Wallace, W. D..

5 recordsLinked to original sources

bioRxiv2024

Cell of origin alters myeloid-mediated immunosuppression in lung adenocarcinoma

Solid carcinomas are often highly heterogenous cancers, arising from multiple epithelial cells of origin. Yet, how the cell of origin influences the response of the tumor microenvironment is poorly understood. Lung adenocarcinoma (LUAD) arises in the distal alveolar epithelium which is populated primarily by alveolar epithelial type I (AT1) and type II (AT2) cells. It has been previously reported that Gramd2+ AT1 cells can give rise to a histologically-defined LUAD that is distinct in pathology and transcriptomic identity from that arising from Sftpc+ AT2 cells1,2. To determine how cells of origin influence the tumor immune microenvironment (TIME) landscape, we comprehensively characterized transcriptomic, molecular, and cellular states within the TIME of Gramd2+ AT1 and Sftpc+ AT2-derived LUAD using KRASG12D oncogenic driver mouse models. Myeloid cells within the Gramd2+AT1-derived LUAD TIME were increased, specifically, immunoreactive monocytes and tumor associated macrophages (TAMs). In contrast, the Sftpc+ AT2 LUAD TIME was enriched for Arginase-1+ myeloid derived suppressor cells (MDSC) and TAMs expressing profiles suggestive of immunosuppressive function. Validation of immune infiltration was performed using flow cytometry, and intercellular interaction analysis between the cells of origin and major myeloid cell populations indicated that cell-type specific markers SFTPD in AT2 cells and CAV1 in AT1 cells mediated unique interactions with myeloid cells of the differential immunosuppressive states within each cell of origin mouse model. Taken together, Gramd2+ AT1-derived LUAD presents with an anti-tumor, immunoreactive TIME, while the TIME of Sftpc+ AT2-derived LUAD has hallmarks of immunosuppression. This study suggests that LUAD cell of origin influences the composition and suppression status of the TIME landscape and may hold critical implications for patient response to immunotherapy.

cancer biology↗

bioRxiv2022

Alveolar epithelial type 1 cells serve as a cell of origin for lung adenocarcinoma with distinct molecular and phenotypic presentation

Lung adenocarcinoma (LUAD) is the most common subtype of cancer arising in the distal lung. LUAD encompasses several pathologic subtypes, each with differing clinical outcomes and biological behaviors. However, the molecular and cellular underpinnings of the different subtypes are largely unknown. Understanding which cell populations in the distal lung contribute to LUAD could provide insights into the marked heterogeneity in pathologic features, clinical presentation and responses to therapy of LUAD. Differential expression analysis of lung adenocarcinoma transcriptomes from The Cancer Genome Atlas revealed distinct alveolar epithelial type 1 (AT1) and alveolar epithelial type 2 (AT2) cell signatures within human LUAD with significantly different survival outcomes between tumors expressing AT2 and AT1 gene signatures, suggesting AT1 cells might contribute to a subset of LUAD cases. To address this, we tested the ability of AT1 cells to give rise to LUAD following induction of KrasG12D, a known oncogenic driver of human LUAD. Activation of KrasG12D in Gram-domain containing 2 (Gramd2)+ AT1 cells gave rise to multiple LUAD lesions, primarily of papillary histology. In contrast, activation of KrasG12D in surfactant protein C (Sftpc+) AT2 cells resulted in LUAD lesions of lepidic histology. Immunohistochemistry established that Gramd2:KrasG12D lesions were of primary lung origin and not metastatic events. Spatial transcriptomic profiling revealed distinct pathway alterations within Gramd2- and Sftpc-derived LUAD. Immunofluorescence confirmed differences observed in the spatial transcriptomic analysis in expression patterns and distribution of cell-specific markers depending on cell of origin, while universal upregulation of the Krt8 intermediate cell state marker was observed. Our results are consistent with Gramd2+ AT1 cells serving as a putative cell of origin for LUAD and suggest that LUAD may be a collection of adenocarcinomas that share a common location within the distal lung but arise from different cells of origin.

cancer biology↗

bioRxiv2021

Neutrophil-epithelial interactions augment infectivity and pro-inflammatory responses to SARS-CoV-2 infection

In response to viral infection, neutrophils release inflammatory mediators as part of the innate immune response, contributing to pathogen clearance through virus internalization and killing. Pre-existing co- morbidities correlating to incidence of severe COVID-19 are associated with chronic airway neutrophilia. Furthermore, examination of COVID-19 explanted lung tissue revealed a series of epithelial pathologies associated with the infiltration and activation of neutrophils, indicating neutrophil activity in response to SARS- CoV-2 infection. To determine the impact of neutrophil-epithelial interactions on the infectivity and inflammatory responses to SARS-CoV-2 infection, we developed a co-culture model of airway neutrophilia. SARS-CoV-2 infection of the airway epithelium alone does not result in a notable pro-inflammatory response from the epithelium. The addition of neutrophils induces the release of proinflammatory cytokines and stimulates a significantly augmented pro-inflammatory response subsequent SARS-CoV-2 infection. The resulting inflammatory response is polarized with differential release from the apical and basolateral side of the epithelium. Additionally, the integrity of the epithelial barrier is impaired with notable epithelial damage and infection of basal stem cells. This study reveals a key role for neutrophil-epithelial interactions in determining inflammation and infectivity in response to SARS-CoV-2 infection.

cell biology↗

bioRxiv2020

Development of novel in vitro human alveolar epithelial cell models to study distal lung biology and disease

Many acute and chronic lung diseases affect the distal lung alveoli. Although airway-derived human cell lines exist, alveolar epithelial cell (AEC)-derived lines are needed to better model these diseases. We have generated and characterized novel immortalized cell lines derived from human AECs. They grow as epithelial monolayers expressing lung progenitor markers SOX9 and SOX2, with little to no expression of mature AEC markers. Co-cultured in 3-dimensions (3D) with lung fibroblasts, the cells form NKX2-1+ organoids expressing mature AEC markers AQP5 and GPRC5A. Single-cell RNA sequencing of an AEC line in 2D versus 3D revealed increased cellular heterogeneity and induction of cytokine and lipoprotein signaling, consistent with organoid formation. Activating WNT and FGF pathways resulted in larger organoids. Our approach appears to yield lung progenitor lines that retain a genetic and structural memory of their alveolar cell lineage despite long-term expansion and whose differentiation may be modulated under various 3D conditions. These cell lines provide a valuable new system to model the distal lung in vitro.

cell biology↗

bioRxiv2020

Single-cell characterization of subsolid and solid lesions in the lung adenocarcinoma spectrum

Determining the clinical significance of CT scan-detected subsolid pulmonary nodules requires an understanding of the molecular and cellular features that may foreshadow disease progression. We studied the alterations at the transcriptome level in both immune and non-immune cells, utilizing single-cell RNA sequencing, to compare the microenvironment of subsolid, solid, and non-involved lung tissues from surgical resection specimens. This evaluation of early spectrum lung adenocarcinoma reveals a significant decrease in the cytolytic activities of natural killer and natural killer T cells, accompanied by a reduction of effector T cells as well as an increase of CD4+ regulatory T cells in subsolid lesions. Characterization of non-immune cells revealed that both cancer-associated alveolar type 2 cells and fibroblasts contribute to the deregulation of the extracellular matrix, potentially affecting immune infiltration in subsolid lesions through ligand-receptor interactions. These findings suggest a decrement of immune surveillance in subsolid lesions.

cancer biology↗