Delineating the dynamic evolution from preneoplasia to invasive lung adenocarcinoma by integrating single-cell RNA sequencing and spatial transcriptomics

Abstract

The cell ecology and spatial niche implicated in the dynamic and sequential process of lung adenocarcinoma (LUAD) from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and subsequent invasive adenocarcinoma (IAC) have not yet been elucidated. Here, we performed an integrative analysis of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to characterize the cell atlas of the invasion trajectory of LUAD. We found that the UBE2C + cancer cell subpopulation constantly increased during the invasive process of LUAD with remarkable elevation in IAC, and its spatial distribution was in the peripheral cancer region of the IAC, representing a more malignant phenotype. Furthermore, analysis of the TME cell type subpopulation showed a constant decrease in mast cells, monocytes, and lymphatic endothelial cells, which were implicated in the whole process of invasive LUAD, accompanied by an increase in NK cells and MALT B cells from AIS to MIA and an increase in Tregs and secretory B cells from MIA to IAC. Notably, for AIS, cancer cells, NK cells, and mast cells were colocalized in the cancer region; however, for IAC, Tregs colocalized with cancer cells. Finally, communication and interaction between cancer cells and TME cell-induced constitutive activation of TGF-β signaling were involved in the invasion of IAC. Therefore, our results reveal the specific cellular information and spatial architecture of cancer cells and TME subpopulations, as well as the cellular interaction between them, which will facilitate the identification and development of precision medicine in the invasive process of LUAD from AIS to IAC.

Behind the Indolent Facade: Uncovering the Molecular Features and Malignancy Potential in Lung Minimally Invasive Adenocarcinoma by Single‐Cell Transcriptomics

“…The proportion of SPP1 + TAM cells was higher in IA compared to N, but not greater in MIA than N. In contrast, the proportion of CTSB + TAM cells in both IA and MIA were significantly higher than that in N, suggesting that CTSB + TAM cells, instead of SPP1 + TAM cells, play a crucial role in MIA (Figure 5I). Consistent with these results, we found that the expression of CTSB was higher in the cells from MIA samples compared to that from IA sample in GSE189487 datasets [14] (Figure 5J), while the expression of SPP1 was lower in the cells from MIA samples compared to that from IA samples (Figure 5K). An integrated dataset of 719 LUAD patients corrected by Gyorffy [20] showed that high expression levels of both CTSB and SPP1 significantly was associated with poor survival, highlighting the critical role of CTSB + and SPP1 + TAM in the progression of LUAD (Figure 5L,M).…”

“…The number and function of CD8 + T cells in LUAD decline with disease progression, but their status in MIA remains controversial. [12][13][14][15]27] Here, we showed that MIA has a similar immune infiltration environment to normal tissue, but both the quantity and quality of CD8 + T cells decrease from MIA to IA. The anti-tumor microenvironment of MIA may help restrain tumor growth and confer its indolent nature.…”

ELOVL6 is associated with immunosuppression in lung adenocarcinoma through bioinformatics analysis

“…[28,29] What more, some researchers found that the subpopulation of cancer cells expressing UBE2C increased during the invasion of lung adenocarcinoma cells into normal tissues, distributed in the periphery of cancerous tissues, and possessed strong invasiveness. [30] And the expression level of UBE2C gradually increases as the degree of tumor differentiation decreases. [31] The emergence of drug resistance during the treatment of tumors often indicates a poorer prognosis for patients.…”

Spatially Resolved Transcriptomics Technology Facilitates Cancer Research

“…[ 90 ] Increased Tregs and decreased monocytes have been shown to activate tumor‐associated pathways, thereby promoting early LUAD invasion. [ 74 ] Liver is the most important target organ for CRC metastasis, and colorectal cancer liver metastasis (CRLM) has a highly heterogeneous and suppressive immune microenvironment, which is one of the bottlenecks and difficulties for CRC treatment. By scRNA‐seq and SRT sequencing of paired samples of CRC and liver metastasis, Wu et al.…”