Multiomics Profiling of Esophageal Cancer Development: Could Single-cell Transcriptomic and Epigenetic Analyses Extend our Understanding?

By Stuart P. Atkinson

Graphical Abstract from Strasser et al., outlining premalignancy dysfunction and dysregulation in esophogeal cancer.

Could a Detailed Description of Disease Development Highlight Treatments for Esophageal Cancer?

Patients with Barrett's esophagus (Nowicki-Osuch et al.), a metaplastic state representing an adaptive mucosal response to chronic inflammation, suffer from a hugely increased risk of developing esophageal adenocarcinoma (Smyth et al. and Krishnamoorthi et al.). Encouragingly, the relative ease of collecting patient-matched tissue samples representing all clinical histological/diagnostic stages at a single time point in a single patient has supported the publication of multiple studies describing esophageal cancer development. These studies included a recent collaborative effort published in Developmental Cell (Strasser et al.).

Single-cell RNA-seq data of ~300,000 cells from 26 patients, surveying 9 coarse cell classes and 35 cell types and states. Figure from Strasser et al..

Can Single-Cell Multiomic Profiles of Disease Development Identify Therapeutic Targets?

The findings of this new study reveal concomitant alterations to epithelial and stromal compartments during progression, the emergence of immunosuppressive carcinoma-associated fibroblasts (CAFs) during metaplasia, and the establishment of an immunosuppressive microenvironment during malignant progression. The single-cell resolution and tissue-level molecular profiling linked molecular markers of malignant progression to cellular origins and shifts in cell-type composition and tissue architectures. Could the additional integration of simultaneous profiling of transcriptomics and epigenetics afforded by applying Paired-Tag technology from Epigenome Technologies further our understanding of esophageal cancer and move us closer to identifying potential treatment avenues for the seventh most common cancer worldwide (Uhlenhopp et al.)?

Changes in cell type proportions identified between normal esophagus (mNE - baseline), normal stomach (mNS), metaplastic (M), dysplastic (D), and malignant (T) samples. Single-cell embeddings are shown along with cluster proportions, marker genes, and per-state sample-of-origin. Figure from Strasser et al..

Study Reveals how Stromal Cell, ECM, and Tissue Stiffness Alterations Accompany the Appearance of CAFs

In brief, the results revealed that the metaplastic replacement of epithelial cell composition and architecture associated with disease progression occurred alongside alterations to stromal cells, ECM, and tissue stiffness; furthermore, the appearance of CAFs accompanied this change in pre-cancerous metaplasia. The CAFs produced the immunosuppressive protein POSTN, whose expression shifted from vascular to stromal cells, consistent with the emergence of an immunosuppressive microenvironment evident in cell neighborhoods enriched for immunoregulatory natural killer and T regulatory cells.

Analysis of physical proximity of cell types along stages of dysfunction and malignancy in the esophegus, along with a model of how community dysregulation (shannon diversity) influences normal-to-malignancy progression. Figure from Strasser et al..

Could Simultaneous Single-cell Transcriptomic and Epigenetic Analyses Extend our Understanding?

While this study did not involve epigenetic analysis, an understanding of the single-cell gene regulatory programs active in each cell type at each level of disease progression and their relation to the transcriptomic profiles of the same single cell may provide an even more detailed description of how normal tissues pass through a metaplastic state before succumbing to esophageal adenocarcinoma.

Paired-Tag technology from Epigenome Technologies generates joint epigenetic and transcriptomic profiles at single-cell resolution and detects histone modifications and RNA transcripts in individual nuclei with comparable efficiency to single-nucleus RNA-seq/ChIP-seq assays while avoiding the need for cell sorting. The implementation of Paired-Tag technology may enable these researchers to define the very beginnings of esophageal cancer development and identify the critical regulatory elements controlling passage from one developmental stage to the next. These details may represent the key to the development of novel treatment strategies for this unfortunately common form of cancer.