S100a4+ alveolar macrophages accelerate the progression of precancerous atypical adenomatous hyperplasia by promoting the angiogenic function regulated by fatty acid metabolism

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    eLife Assessment

    This is an important study demonstrating the importance of S100A4+ alveolar macrophages in the earlier stages of tumour development and suggesting a role in angiogenesis. As such this convincing study is of interest to cancer biologists focused on early tumour development and those interested in the development of therapeutics that may specifically target early cancers.

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Abstract

Lung cancer is preceded by premalignant lesions, and what factors drive this transformation and the potential regulatory mode in the context of tumor initiation remain to be elucidated. In the course of precancerous lesions, we found a phasic shift in metabolic patterns. Macrophages are a heterogeneous cell population with high plasticity in the tumor microenvironment. Single-cell interaction and metabolic analyses highlighted a cellular state, S100a4 + alveolar macrophages, which exhibited distinct fatty acid metabolic activity, such as palmitic acid metabolism, at the atypical adenomatous hyperplasia stage, accompanied by an angiogenic-promoting function in a pre-neoplastic setting. These findings were reproducible in human single-cell transcriptomes and had been confirmed by histopathological staining and in vitro cell coculture assays. Taken together, the results from this study demonstrated that the S100a4 + alveolar macrophage subset contributes to tumorigenesis by altering its metabolic state, suggesting that metabolic interventions targeting this cell state in the early stage of disease may delay neoplastic transformation of the lung epithelium.

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  1. eLife Assessment

    This is an important study demonstrating the importance of S100A4+ alveolar macrophages in the earlier stages of tumour development and suggesting a role in angiogenesis. As such this convincing study is of interest to cancer biologists focused on early tumour development and those interested in the development of therapeutics that may specifically target early cancers.

  2. Reviewer #1 (Public review):

    Summary:

    In this paper, the authors have leveraged Single-cell RNA sequencing of the various stages of evolution of lung adenocarcinoma to identify the population of macrophages that contribute to tumor progression. They show that S100a4+ alveolar macrophages, active in fatty acid metabolic activity, such as palmitic acid metabolism, seem to drive atypical adenomatous hyperplasia (AAH) stage. These macrophages also seem to induce angiogenesis promoting tumor growth. Similar types of macrophage infiltration were demonstrated in the progression of the human lung adenocarcinomas.

    Comments on revised version:

    The authors have satisfactorily addressed my main concerns.

    The only weakness is that infusion of S100a4+ macrophages seem not to affect tumor growth when introduced to the intratracheal route. This …

  3. Reviewer #2 (Public review):

    Summary:

    The work aims to further understand the role of macrophages in lung precancer/lung cancer evolution

    Strengths:

    (1) The use of single-cell RNA seq to provide comprehensive characterisation.

    (2) Characterisation of cross-talk between macrophages and the lung precancerous cells.

    (3) Functional validation of the effects of S100a4+ cells on lung precancerous cells using in vitro assays.

    (4) Validation in human tissue samples of lung precancer / invasive lesions.

    Weaknesses identified previously:

    (1) The authors need to provide clarification of several points in the text.

    (2) The authors need to carefully assess their assumptions regarding the role of macrophages in angiogenesis in precancerous lesions.

    (3) The authors should discuss more broadly the current state of anti-macrophage therapies in the clinic.

  4. Author response:

    The following is the authors’ response to the original reviews

    Public Reviews:

    Reviewer #1 (Public review):

    Summary:

    In this paper, the authors have leveraged Single-cell RNA sequencing of the various stages of the evolution of lung adenocarcinoma to identify the population of macrophages that contribute to tumor progression. They show that S100a4+ alveolar macrophages, active in fatty acid metabolic activity, such as palmitic acid metabolism, seem to drive the atypical adenomatous hyperplasia (AAH) stage. These macrophages also seem to induce angiogenesis promoting tumor growth. Similar types of macrophage infiltration were demonstrated in the progression of the human lung adenocarcinomas.

    Strengths:

    Identification of the metabolic pathways that promote angiogenesis-dependent progression of lung adenocarcinomas from …

  5. eLife Assessment

    This is an important study demonstrating the importance of S100A4+ alveolar macrophages in the earlier stages of tumour development and suggesting a role in angiogenesis. As such this solid study is of interest to cancer biologists focused on early tumour development and those interested in the development of therapeutics that may specifically target early cancers.

  6. Reviewer #1 (Public review):

    Summary:

    In this paper, the authors have leveraged Single-cell RNA sequencing of the various stages of the evolution of lung adenocarcinoma to identify the population of macrophages that contribute to tumor progression. They show that S100a4+ alveolar macrophages, active in fatty acid metabolic activity, such as palmitic acid metabolism, seem to drive the atypical adenomatous hyperplasia (AAH) stage. These macrophages also seem to induce angiogenesis promoting tumor growth. Similar types of macrophage infiltration were demonstrated in the progression of the human lung adenocarcinomas.

    Strengths:

    Identification of the metabolic pathways that promote angiogenesis-dependent progression of lung adenocarcinomas from early atypical changes to aggressive invasive phenotype could lead to the development of …

  7. Reviewer #2 (Public review):

    Summary:

    The work aims to further understand the role of macrophages in lung precancer/lung cancer evolution

    Strengths:

    (1) The use of single-cell RNA seq to provide comprehensive characterisation.

    (2) Characterisation of cross-talk between macrophages and the lung precancerous cells.

    (3) Functional validation of the effects of S100a4+ cells on lung precancerous cells using in vitro assays.

    (4) Validation in human tissue samples of lung precancer / invasive lesions.

    Weaknesses:

    (1) The authors need to provide clarification of several points in the text.

    (2) The authors need to carefully assess their assumptions regarding the role of macrophages in angiogenesis in precancerous lesions.

    (3) The authors should discuss more broadly the current state of anti-macrophage therapies in the clinic.