Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing

Sinjab, Ansam; Han, Guangchun; Treekitkarnmongkol, Warapen; Hara, Kieko; Brennan, Patrick McKinley; Dang, Minghao; Hao, Dapeng; Wang, Ruiping; Dai, Enyu; Dejima, Hitoshi; Zhang, Jiexin; Bogatenkova, Elena; Sánchez-Espiridión, Beatriz; Chang, Kyle; Little, Danielle R.; Bazzi, Samer; Tran, Linh M.; Krysan, Kostyantyn; Behrens, Carmen; Duose, Dzifa Y.; Parra, Edwin R.; Raso, Maria Gabriela; Solis, Luisa M.; Fukuoka, Junya; Sepesi, Boris; Cascone, Tina; Byers, Lauren A.; Gibbons, Don L.; Chen, Jichao; Moghaddam, Seyed Javad; Ostrin, Edwin J.; Rosen, Daniel; Heymach, John V.; Scheet, Paul; Dubinett, Steven M.; Fujimoto, Junya; Wistuba, Ignacio I.; Stevenson, Christopher S.; Spira, Avrum; Wang, Linghua; Kadara, Humam

doi:10.1158/2159-8290.cd-20-1285

Cited by 84 publications

(129 citation statements)

References 47 publications

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“…Our data, in consensus with the existing literature, suggested an increase in basal and aberrant basaloid cells in the distal lung epithelium of IPF patients, which have been in the past identified by their cytokeratin 5 (CK5, the protein product of KRT5 mRNA) intracellular or NGFR cell surface expression 50 . First, we determined by flow cytometry the expression of the CK5 protein in the epithelial compartment of six donor and six IPF lungs.…”

Section: Basal Cell Markers Expression In Donor and Ipf Lungsupporting

confidence: 91%

“…We further confirm by flow cytometry and immunofluorescence analysis the CK5 pos cell expansion in IPF, and show that CK5 and NGFR expression define two distinct basal cell populations with differential behavior in IPF. The increased expression in IPF of CD24, a cell surface marker known to be highly expressed in cancer cells 50 and aberrant epithelial cells in IPF 30,31 , is also confirmed, offering a potential cell surface marker to sub-type together with Lysotracker incorporation various populations of epithelial cells in donor and IPF lung.…”

Section: Discussionmentioning

confidence: 65%

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Differential Lysotracker Uptake Defines Two Populations of Distal Epithelial Cells in Idiopathic Pulmonary Fibrosis

Wasnick¹,

Shalashova²,

Wilhelm³

et al. 2021

Preprint

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Idiopathic lung fibrosis (IPF) is a progressive and fatal degenerative lung disease of unknown etiology. Although in its final stages it implicates in a reactive manner all lung cell types, the initial damage involves the alveolar epithelial compartment, in particular the alveolar epithelial type 2 cells (AEC2s). AEC2s serve dual progenitor and surfactant secreting functions, both of which are deeply impacted in IPF. Thus, we hypothesize that the size of the surfactant processing compartment, as measured by Lysotracker incorporation, allows the identification of different epithelial states in the IPF lung. Flow cytometry analysis of epithelial Lysotracker incorporation delineates two populations (Lysohigh and Lysolow) of AEC2s which behave in a compensatory manner during bleomycin injury and in the donor/IPF lung. Employing flow cytometry and transcriptomic analysis of cells isolated from donor and IPF lungs, we demonstrate that the Lysohigh population expresses all classical AEC2 markers and is drastically diminished in IPF. The Lysolow population, which is increased in proportion in IPF, co-expresses AEC2s and basal cell markers resembling the phenotype of the previously identified intermediate AEC2 population in the IPF lung. In that regard, we provide an in-depth flow-cytometry characterization of Lysotracker uptake, HTII-280, proSP-C, mature SP-B, NGFR, KRT5 and CD24 expression in human lung epithelial cells. Combining functional analysis with extra- and intra- cellular marker expression and transcriptomic analysis, we advance the current understanding of epithelial cell behavior and fate in lung fibrosis.

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Section: Basal Cell Markers Expression In Donor and Ipf Lungsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 65%

Differential Lysotracker Uptake Defines Two Populations of Distal Epithelial Cells in Idiopathic Pulmonary Fibrosis

Wasnick¹,

Shalashova²,

Wilhelm³

et al. 2021

Preprint

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show abstract

“…ScRNA-seq analysis of 10 normal lung tissues and 10 fresh LUAD tissues found that the TME was composed of cancer-associated myofibroblasts, exhausted CD8 + T cells, proinflammatory monocyte-derived macrophages, plasmacytoid dendritic cells, myeloid dendritic cells, anti-inflammatory monocyte-derived macrophages, normal-like myofibroblasts, NK cells, and conventional T cells ( 69 ). Multi-region of five early-stage LUADs and 14 multi-region normal lung tissues found that the Treg + cells are increased in normal tissues with proximity to LUAD and the signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells were decreased ( 37 ).…”

Section: Application Of Single-cell Technologies In the Early Stage Of Lung Cancermentioning

confidence: 99%

Deciphering the Immune–Tumor Interplay During Early-Stage Lung Cancer Development via Single-Cell Technology

Chen

Liu

et al. 2022

Front. Oncol.

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Lung cancer is the leading cause of cancer-related death worldwide. Cancer immunotherapy has shown great success in treating advanced-stage lung cancer but has yet been used to treat early-stage lung cancer, mostly due to lack of understanding of the tumor immune microenvironment in early-stage lung cancer. The immune system could both constrain and promote tumorigenesis in a process termed immune editing that can be divided into three phases, namely, elimination, equilibrium, and escape. Current understanding of the immune response toward tumor is mainly on the “escape” phase when the tumor is clinically detectable. The detailed mechanism by which tumor progenitor lesions was modulated by the immune system during early stage of lung cancer development remains elusive. The advent of single-cell sequencing technology enables tumor immunologists to address those fundamental questions. In this perspective, we will summarize our current understanding and big gaps about the immune response during early lung tumorigenesis. We will then present the state of the art of single-cell technology and then envision how single-cell technology could be used to address those questions. Advances in the understanding of the immune response and its dynamics during malignant transformation of pre-malignant lesion will shed light on how malignant cells interact with the immune system and evolve under immune selection. Such knowledge could then contribute to the development of precision and early intervention strategies toward lung malignancy.

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“…Therapeutic vaccines activate the T cell to recognize cancerous neoantigens, initiating an immune response for individualized vaccination ( 7 ). Therefore, LUAD requires combined therapy and we should classify the LUAD population with different molecular characteristics ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Potential Immune Biomarker Candidates and Immune Subtypes of Lung Adenocarcinoma for Developing mRNA Vaccines

et al. 2021

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mRNA vaccines against cancer have advantages in safety, improved therapeutic efficacy, and large-scale production. Therefore, our purpose is to identify immune biomarkers and to analyze immune status for developing mRNA vaccines and selecting appropriate patients for vaccination. We downloaded clinical information and RNA-seq data of 494 LUAD patients from TCGA. LUAD mutational information was hierarchically clustered by NMF package (Version 0.23.0). DeconstructSigs package (Version 1.8.0) and NMF consistency clustering were used to identify mutation signatures. Maftools package (Version 2.6.05) was used to select LUAD-related immune biomarkers. TIMER was used to discuss the correlation between genetic mutations and cellular components. Unsupervised clustering Pam method was used to identify LUAD immune subtypes. Log-rank test and univariate/multivariate cox regression were used to predict the prognosis of immune subtypes. Dimensionality reduction analysis was dedicated to the description of LUAD immune landscape. LUAD patients are classified into four signatures: T >C, APOBEC mutation, age, and tobacco. Then, GPRIN1, MYRF, PLXNB2, SLC9A4, TRIM29, UBA6, and XDH are potential LUAD-related immune biomarker candidates to activate the immune response. Next, we clustered five LUAD-related immune subtypes (IS1–IS5) by prognostic prediction. IS3 showed prolonged survival. The reliability of our five immune subtypes was validated by Thorsson’s results. IS2 and IS4 patients had high tumor mutation burden and large number of somatic mutations. Besides, we identified that immune subtypes of cold immunity (patients with IS2 and IS4) are ideal mRNA vaccination recipients. Finally, LUAD immune landscape revealed immune cells and prognostic conditions, which provides important information to select patients for vaccination. GPRIN1, MYRF, PLXNB2, SLC9A4, TRIM29, UBA6, and XDH are potential LUAD-related immune biomarker candidates to activate the immune response. Patients with IS2 and IS4 might potentially be immunization-sensitive patients for vaccination.

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Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing

Cited by 84 publications

References 47 publications

Differential Lysotracker Uptake Defines Two Populations of Distal Epithelial Cells in Idiopathic Pulmonary Fibrosis

Differential Lysotracker Uptake Defines Two Populations of Distal Epithelial Cells in Idiopathic Pulmonary Fibrosis

Deciphering the Immune–Tumor Interplay During Early-Stage Lung Cancer Development via Single-Cell Technology

Potential Immune Biomarker Candidates and Immune Subtypes of Lung Adenocarcinoma for Developing mRNA Vaccines

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