Single-cell transcriptomic analyses provide insights into the cellular origins and drivers of brain metastasis from lung adenocarcinoma

Abstract

Background Brain metastasis (BM) is the most common intracranial malignancy causing significant mortality, and lung cancer is the most common origin of BM. However, the cellular origins and drivers of BM from lung adenocarcinoma (LUAD) have yet to be defined. Methods The cellular constitutions were characterized by single-cell transcriptomic profiles of 11 LUAD primary tumor (PT) and 10 BM samples (GSE131907). Copy number variation (CNV) and clonality analysis were applied to illustrate cellular origins of BM tumors. Brain metastasis-associated epithelial cells (BMAECs) were identified by pseudotime trajectory analysis. By using machine-learning algorithms, we developed the BM-index representing the relative abundance of BMAECs in the bulk RNA-seq data, indicating high risk of BM. Therapeutic drugs targeting BMAECs were predicted based on the drug sensitivity data of cancer cell lines. Results Differences in macrophages and T cells between PTs and BMs were investigated by single-cell RNA (scRNA) and immunohistochemistry and immunofluorescence data. CNV analysis demonstrated BM was derived from subclones of PT with a gain of chromosome 7. We then identified BMAECs and its biomarker, S100A9. Immunofluorescence indicated strong correlations of BMAECs with metastasis and prognosis evaluated by the paired PT and BM samples from Peking Union Medical College Hospital (PUMCH). We further evaluated the clinical significance of BM-index and identified 7 drugs that potentially target BMAECs. Conclusions This study clarified possible cellular origins and drivers of metastatic LUAD at single cell level, and laid a foundation for early detections of LUAD patients with a high risk of BM.

Identification of distinct tumor cell patterns with single-cell RNA sequencing integrating primary lung adenocarcinoma and brain metastasis tumor

“…Wang et al ( 23 ) mentioned S100A9 could potentially be a marker gene for brain metastasis-associated epithelial cells, which may be the origin of brain metastasis. However, S100A9 is commonly regarded as a marker of inflammatory cells such as neutrophils or monocytes.…”

“…Metastasis-initiating cells (MICs) can seed metastatic colonies in the distal region, hijacking some of the stem cell pathways to increase the cellular endurance to selective pressure induced by the intracranial microenvironment ( 22 , 23 ). MICs are hard to identify, track and capture, which leads to an exceedingly difficult challenge in characterizing the mechanism of brain metastasis.…”

Bulk RNA-seq and scRNA-seq reveal SLC7A11, a key regulatory molecule of ferroptosis, is a prognostic-related biomarker and highly related to the immune system in lung adenocarcinoma

“…Cell annotation was carried out with the SingleR package [29] and reports from the literature. [30][31][32] Finally, single-cell trajectory analysis was performed with the "Monocle 2 algorithm." [33]…”

Understanding the heterogeneous immune repertoire of brain metastases for designing next‐gen therapeutics

“…[29] These technologies enable researchers to examine the transcriptomic and proteomic signals of rare immune cells at a single-cell resolution from bulk brain cell preparations, allowing them to dissect the characteristics of brain-infiltrating immune cells for the first time. Since 2020, several research groups have utilized these new technologies to study immune cell populations in brain tumors and metastases, [10,[30][31][32][33] leading to some interesting findings. For instance, Karimi et al discovered a correlation between the abundance of myeloperoxidase-positive macrophages and the long-term survival of glioblastoma patients.…”