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Curated Papers > In recent years, there has been significant research on "single-cell sequencing" with high impact factors (IF≥30) over the past five years.

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

Literature Information ​

DOI10.1158/2159-8290.CD-20-1285
PMID33972311
JournalCancer discovery
Impact Factor33.3
JCR QuartileQ1
Publication Year2021
Times Cited78
KeywordsLung Adenocarcinoma, Single-Cell RNA Sequencing, Cell Heterogeneity, Spatial Ecology, Transcriptomic Features
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN2159-8274
Pages2506-2523
Issue11(10)
AuthorsAnsam Sinjab, Guangchun Han, Warapen Treekitkarnmongkol, Kieko Hara, Patrick M Brennan, Minghao Dang, Dapeng Hao, Ruiping Wang, Enyu Dai, Hitoshi Dejima, Jiexin Zhang, Elena Bogatenkova, Beatriz Sanchez-Espiridion, Kyle Chang, Danielle R Little, Samer Bazzi, Linh M Tran, Kostyantyn Krysan, Carmen Behrens, Dzifa Y Duose, Edwin R Parra, Maria Gabriela Raso, Luisa M Solis, Junya Fukuoka, Jianjun Zhang, Boris Sepesi, Tina Cascone, Lauren Averett Byers, Don L Gibbons, Jichao Chen, Seyed Javad Moghaddam, Edwin J Ostrin, Daniel Rosen, John V Heymach, Paul Scheet, Steven M Dubinett, Junya Fujimoto, Ignacio I Wistuba, Christopher S Stevenson, Avrum Spira, Linghua Wang, Humam Kadara

TL;DR ​

This study provides a spatial atlas of lung adenocarcinoma (LUAD) evolution by performing single-cell RNA sequencing on 186,916 cells from early-stage LUADs and adjacent normal lung tissues, revealing significant geospatial changes in cellular lineages and states. The findings highlight increased T regulatory cells near tumors and decreased cytotoxic immune cells, suggesting potential therapeutic targets for early LUAD interception.

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Lung Adenocarcinoma · Single-Cell RNA Sequencing · Cell Heterogeneity · Spatial Ecology · Transcriptomic Features

Abstract ​

Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial CD24, which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. SIGNIFICANCE: The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception.This article is highlighted in the In This Issue feature, p. 2355.

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Primary Questions Addressed ​

  1. How does the geospatial architecture of LUAD influence treatment strategies for early-stage lung cancer?
  2. What implications do the findings on T regulatory cell phenotypes have for immunotherapy approaches in LUAD?
  3. In what ways could the identified transcriptional lineage-plasticity programs affect the prognosis of LUAD patients?
  4. How can the increased expression of epithelial CD24 in the LUAD ligand-receptor interactome be targeted for therapeutic interventions?
  5. What are the potential impacts of intratumor cell heterogeneity on the development of resistance to therapies in lung adenocarcinoma?

Key Findings ​

Research Background and Objectives ​

Lung adenocarcinoma (LUAD) represents a major subtype of lung cancer, yet the spatial architecture of individual cell populations during its evolution remains poorly understood. This study aims to elucidate the geospatial dynamics of cellular lineages and transcriptomic features in early-stage LUAD and their surrounding normal lung tissues.

Main Methods/Materials/Experimental Design ​

The researchers conducted single-cell RNA sequencing (scRNA-seq) on a total of 186,916 cells derived from five early-stage LUAD samples and 14 multiregion normal lung tissues. The design allowed for the examination of cellular states and lineage relationships across spatial proximities from tumors to adjacent normal tissues.

Mermaid diagram

Key Results and Findings ​

  • Cellular Heterogeneity: LUADs exhibited significant intratumor heterogeneity, indicating diverse cellular states within single tumor sites.
  • T Regulatory Cells: Increased T regulatory cell phenotypes were observed in normal tissues adjacent to LUAD, while cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells were reduced.
  • Ligand-Receptor Interactome: The study identified elevated expression of epithelial CD24 in LUAD, which is associated with protumor characteristics.
FindingDescription
Cellular Lineage DynamicsEvolution of cellular states from normal to LUAD tissues
Immune Cell Population ChangesIncreased T regulatory cells; decreased cytotoxic CD8+ T cells and others
Epithelial CD24 ExpressionHigher levels in LUAD, linked to protumor activity

Main Conclusions/Significance/Innovation ​

This research provides a spatial atlas of LUAD evolution, highlighting the dynamic interplay between tumor and normal tissue cellular environments. The identification of specific immune cell changes and protumor markers like CD24 presents new avenues for therapeutic interventions and early detection strategies in LUAD.

Research Limitations and Future Directions ​

While the study offers significant insights, limitations include the focus on early-stage LUAD and a limited number of samples. Future research should expand the sample size and include late-stage LUAD to validate findings. Additionally, functional studies are necessary to explore the implications of identified cellular interactions and immune landscape alterations in LUAD progression and treatment responses.

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Literatures Citing This Work ​

  1. Applications of single-cell sequencing in cancer research: progress and perspectives. - Yalan Lei;Rong Tang;Jin Xu;Wei Wang;Bo Zhang;Jiang Liu;Xianjun Yu;Si Shi - Journal of hematology & oncology (2021)
  2. Tumor Immunology and Immunotherapy of Non-Small-Cell Lung Cancer. - Tina Cascone;Jared Fradette;Monika Pradhan;Don L Gibbons - Cold Spring Harbor perspectives in medicine (2022)
  3. Lung Cancer Computational Biology and Resources. - Ling Cai;Guanghua Xiao;David Gerber;John D Minna;Yang Xie - Cold Spring Harbor perspectives in medicine (2022)
  4. Weighted Gene Co-Expression Network Analysis and Treatment Strategies of Tumor Recurrence-Associated Hub Genes in Lung Adenocarcinoma. - Zhengze Shen;Shengwei Liu;Jie Liu;Jingdong Liu;Caoyuan Yao - Frontiers in genetics (2021)
  5. Potential Immune Biomarker Candidates and Immune Subtypes of Lung Adenocarcinoma for Developing mRNA Vaccines. - Yang Wang;Huaicheng Tan;Ting Yu;Xiaoxuan Chen;Fangqi Jing;Huashan Shi - Frontiers in immunology (2021)
  6. Deciphering the Immune-Tumor Interplay During Early-Stage Lung Cancer Development via Single-Cell Technology. - Wei-Wei Chen;Wei Liu;Yingze Li;Jun Wang;Yijiu Ren;Guangsuo Wang;Chang Chen;Hanjie Li - Frontiers in oncology (2021)
  7. Differential LysoTracker Uptake Defines Two Populations of Distal Epithelial Cells in Idiopathic Pulmonary Fibrosis. - Roxana Maria Wasnick;Irina Shalashova;Jochen Wilhelm;Ali Khadim;Nicolai Schmidt;Holger Hackstein;Andreas Hecker;Konrad Hoetzenecker;Werner Seeger;Saverio Bellusci;Elie El Agha;Clemens Ruppert;Andreas Guenther - Cells (2022)
  8. Single-Cell RNA Sequencing in Lung Cancer: Revealing Phenotype Shaping of Stromal Cells in the Microenvironment. - Jianhong Zhang;Chengyang Song;Ye Tian;Xueying Yang - Frontiers in immunology (2021)
  9. Distinct Immune Gene Programs Associated with Host Tumor Immunity, Neoadjuvant Chemotherapy, and Chemoimmunotherapy in Resectable NSCLC. - Pedro Rocha;Jiexin Zhang;Raquel Laza-Briviesca;Alberto Cruz-Bermúdez;Neus Bota-Rabassedas;Beatriz Sanchez-Espiridon;Katsuhiro Yoshimura;Carmen Behrens;Wei Lu;Ximing Tang;Apar Pataer;Edwin R Parra;Cara Haymaker;Junya Fujimoto;Stephen G Swisher;John V Heymach;Don L Gibbons;J Jack Lee;Boris Sepesi;Tina Cascone;Luisa M Solis;Mariano Provencio;Ignacio I Wistuba;Humam Kadara - Clinical cancer research : an official journal of the American Association for Cancer Research (2022)
  10. Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy. - Sang T Kim;Yanshuo Chu;Mercy Misoi;Maria E Suarez-Almazor;Jean H Tayar;Huifang Lu;Maryam Buni;Jordan Kramer;Emma Rodriguez;Zulekha Hussain;Sattva S Neelapu;Jennifer Wang;Amishi Y Shah;Nizar M Tannir;Matthew T Campbell;Don L Gibbons;Tina Cascone;Charles Lu;George R Blumenschein;Mehmet Altan;Bora Lim;Vincente Valero;Monica E Loghin;Janet Tu;Shannon N Westin;Aung Naing;Guillermo Garcia-Manero;Noha Abdel-Wahab;Hussein A Tawbi;Patrick Hwu;Isabella C Glitza Oliva;Michael A Davies;Sapna P Patel;Jun Zou;Andrew Futreal;Adi Diab;Linghua Wang;Roza Nurieva - Nature communications (2022)

... (68 more literatures)

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