Cell-of-origin is a strong determinant of the fate and pathology of abnormal cells in diseases as cancers1, 2 or fibrosis3. Cell-of-origin, whose features can be retained in evolving abnormal cells4, is therefore a powerful biomarker for early diagnosis and potential therapeutic targets. However, lineage tracing for cell-of-origin is very hard.
Our lab is committed to understand cell fate and its pathogenic changes from the perspective of the epigenome. The single cell Assay for Transposase Accessible Chromatin (scATAC) detects signals at tens of thousands of genomic regions at single cell resolution, and provides comprehensive and delicate epigenomic map for cell identity. We recently optimized the experimental protocol and bioinformatic pipeline for scATAC-seq. Here we set out to test the strategy to trace back cell-of-origin of abnormal cells with cell type-specific epigenome of their potential origin cells.
On Jan 10th, 2022, Wang et al. published the paper “Single-cell chromatin accessibility landscape in kidney identifies additional cell-of-origin in heterogenous papillary renal cell carcinoma” in Nature Communications. We captured the cell type-specific chromatin accessibility landscape of normal human kidney at single-cell resolution. A total of 9460 super-high-quality nuclei were kept after stringent quality controls and 20 cell clusters were annotated which included all the main cell types in the kidney. This provides an integral landscape that is needed to investigate the cell-of-origin. We then apply this landscape to identify the cell-of-origin of papillary renal cell carcinoma (pRCC) which is the most heterogenous type of renal cell carcinoma. With the ATAC-seq profiles of pRCC samples from TCGA5, we find two distinct cell-of-origins. Most of the samples originate from previously proposed proximal tubule (PT) cell, but 4 out of the 34 pRCC are with an unexpected collecting duct principal (CD_PC) cell origin.
Interestingly, we further found pRCCs with CD_PC origin are the more advanced ones and we observed divergent transition paths of these tumor cells from their corresponding cell-of-origin. The development of pRCCs with PT origin show a NOTCH and mTOR signaling pathway-dominant transition. In contrast, pRCCs with CD_PC origin display activation of inflammation and immune-related pathways. This deficiency of mTOR activation in more advanced pRCC explains why current treatments for advanced pRCC such as VEGF- and mTOR-directed therapies6 and the addition of interferon-α7 show only marginal clinical benefits. What’s more, the results also indicate immune checkpoint inhibitors is likely to offer better clinical outcomes.
In summary, our study shows that the pRCC cohort are segregated by different cell-of-origins on molecular characteristics and clinical behaviours. Our results demonstrate that cell type-specific epigenome is valuable for identification of cell-of-origin and pathogenic transition. Although our work was conducted only in pRCC, this strategy can be further extended to many other diseases.
If you are interested to read more about our work, please find the complete study in Nature Communications: https://www.nature.com/articles/s41467-021-27660-3
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- Wang Z, et al. Cell Lineage-Based Stratification for Glioblastoma. Cancer Cell 38, 366-379 e368 (2020).
- Kuppe C, et al. Decoding myofibroblast origins in human kidney fibrosis. Nature 589, 281-286 (2021).
- Levine JH, et al. Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis. Cell 162, 184-197 (2015).
- Corces MR, et al. The chromatin accessibility landscape of primary human cancers. Science 362, 420-+ (2018).
- Choueiri TK, Motzer RJ. Systemic Therapy for Metastatic Renal-Cell Carcinoma. N Engl J Med 376, 354-366 (2017).
- Hudes G, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356, 2271-2281 (2007).