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Cancer Insights – Breast and Lung Cancer

Recent developments in single-cell sequencing technologies lead the path to cancer prevention through precise insights into cancer development

To honor the increasing number of dedicated publications and findings on cancer treatment and prevention, we highlight recent advances in cancer research. Despite a growing knowledge for cancerogenous pathways, much of the heterogeneity within tumors as well as transforming mechanisms at a single-cell level remain elusive. However, single-cell sequencing technologies have improved our understanding of tumor complexity and underlying intercellular interactions throughout recent years.

Cancer is one of the leading causes for death and reduced life expectancy worldwide with approximately 19.3 million new cases per year and almost 10.0 million fatalities each year. In other words, statistically, every fourth individual is expected to develop cancer throughout their lifetime. Unfortunately, the global cancer burden is expected to further rise to 28.4 million cases annually by 2040, which equals an increase by 47% since 2020 [1]. Among the most common cancer types are breast cancer and lung cancer. Thus, fighting cancer and unraveling efficient and suitable therapeutic options remains a central goal of the research community for the upcoming years.

The presence of differences in genetic or epigenetic variants between different malignant cells can be a major obstacle for offering efficient treatment to patients, particularly those with primary tumors and metastases. To shed light into the regulation of lymph node metastasis in breast cancer patients, the group of Xiaoxiang Guan from Nanjing Medical University in China, employed single-cell RNA sequencing to obtain transcriptomic profiles of a total of 30,213 individual cells from primary tumors and lymph nodes [2]. Furthermore, they carried out a single-cell assay for transposase-accessible chromatin (ATAC) sequencing (scATAC-seq) to investigate chromatin accessibility in the single cells obtained from lymph nodes. Combined, these single-cell sequencing data revealed a distinct cell subpopulation with elevated expression levels of chemokine (C-X-C motif) ligand 14 (CXCL14) that occurred in the late pseudo-time according to cell trajectory analysis. Thus, the authors hypothesized that CXCL14 might play an important role in breast cancer with lymph node metastasis. Corroborating this hypothesis, gene expression profiling using microarrays showed increased expression of CXCL14 in breast cancer tissue from patients with lymph node metastasis compared to normal tissue (n=38). Taken together Xu K. et al. used single-cell sequencing to provide evidence for a potential role of CXCL14 in breast cancer with lymph node metastasis, which could serve as a prognostic biomarker in the future.

Using the breast cancer mouse model MMTV-PyMT Jiang G. et al. interrogated the origin and dynamic changes of breast cancer stem-like cells [3]. For this purpose, they created a single-cell atlas of 31,778 cells from tumors of four distinct stages of tumor progression. The authors identified the ERlow epithelial cell lineage as the initiating cell population for tumor growth. Furthermore, they could link a distinct gene expression signature to tumor progression and even clinical outcome. Their data also suggested that diverse infiltrating immune cells exerted immunosuppressive characteristics during tumor progression. Hence, this study presents data regarding the transcriptomic dynamics during tumor progression at single-cell resolution that might help to further understand the molecular mechanisms of breast cancer development and progression.

Also, the field of lung cancer research has made major progress in the past year through applying single-cell sequencing technologies. In a comprehensive talk at the ESHG 2021, Prof. Reinhard Büttner (University Hospital Cologne) shared his expert opinion on how single-cell sequencing can be used in cancer diagnosis and treatment (watch here). His latest research was focused on advanced non-small cell lung cancer (NSCLC) using single-cell sequencing to investigate cell type-specific transcriptome landscape of cancer cells and their tumor microenvironment [4]. Analyzing 42 biopsies and a total of 90,406 single cells the authors identified rare cell types in tumors including follicular dendritic cells and T helper 17 cells. Furthermore, they describe large interpatient heterogeneity in cellular composition of the tumors and describe intercellular signaling networks. Finally, the study correlated tumor heterogeneity with tumor associated neutrophils, while their function in NSCLC remains to be elucidated.

In a retrospective study of NSCLC patients with EGFR mutation Liu S. et al. analyzed the potential benefit of combining targeted therapy with tyrosine kinase inhibitors for EGFR and immunotherapy [5]. They reported that patients with shortened progress-free survival after tyrosine kinase inhibitor treatment showed a better response to immunotherapy than those with longer progress-free survival. Single-cell sequencing revealed that these two groups were also different in their tumor microenvironment. Thus, particularly for second-line treatment of patients that progress fast after the initial EGFR-specific tyrosine kinase inhibitor treatment, combined treatment with immune-checkpoint inhibitors and chemotherapy could be a promising therapeutic option.

Despite these major breakthroughs in cancer research during the past year, we are still only at the beginning of understanding cancer development and progress. Besides traditional methods, single-cell sequencing has proven to be a valuable tool to research tumor heterogeneity, cell type-specific signaling, and to discover novel predictive biomarkers.

[1] Sung H. et al., Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries; CA Cancer J Clin; 2021; 71:209–249.

[2] Xu K, et al., Integrative analyses of scRNA-seq and scATAC-seq reveal CXCL14 as a key regulator of lymph node metastasis in breast cancer; Human Molecular Genetics, 2021; 30,5:370-380.

[3] Jiang, G. et al., Single-cell transcriptomics reveal the heterogeneity and dynamic of cancer stem-like cells during breast tumor progression; 2021; Cell Death Discovery; 12, 979.

[4] Wu, F. et al., Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer; 2021; Nature Communications 12, 2540.

[5] Liu, S. et al., Patients With Short PFS to EGFR-TKIs Predicted Better Response to Subsequent Anti-PD-1/PD-L1 Based Immunotherapy in EGFR Common Mutation NSCLC. Frontiers Oncology. 11:639947. doi: 10.3389/fonc.2021.639947