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

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 strategies to abort tumor progression.

Weaknesses:

(1) Can the authors demonstrate what are the functional specialization of the S100a4+ alveolar macrophages that promote the progression of the AAH to the more aggressive phenotype? What are the factors produced by these unique macrophages that induce tumor progression and invasiveness?

(2) Angiogenic factors are not only produced by the S100a4+ cells but also by pericytes and potentially by the tumor cells themselves. Then, how do these factors aberrantly trigger tumor angiogenesis that drives tumor growth?

(3) It is not clear how abnormal fatty acid uptake by the macrophages drives the progression of tumors.

(4) Does infusion or introduction of S100a4+ polarized macrophages promote the progression of AAH to a more aggressive phenotype?

(5) How does Anxa and Ramp1 induction in inflammatory cells induce angiogenesis and tumor progression?

(6) For the in vitro studies the authors might consider using primary tumor cells and not cell lines.

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.