| Data source |
GEO: GSE115140
|
| Description |
The classic cancer evolution model posits that driver mutations sweep the population sequentially as the complete set of hallmarks are assembled by the neoplastic clone. However, recent work has challenged this model revealing that most tumors contain highly complex dynamics with genetic diversity reflecting distinct clonal architectures. The functional and phenotypic heterogeneity also has been shown to have a crucial influence on the fate of the tumor5–10. However, it is not well understood how distinct tumor clonal populations coexist and function. Here, we study tumor architecture at the level of individual cells by sampling a zebrafish melanoma tumor over time and space. We found that cancer transcriptional programs can be classified to three archetypes, each exploiting the existing neural crest, mature melanocytes, and stress modules, and distinct intra-tumor locations. Strikingly, these archetypes are conserved in human melanoma. Further, we found that the cancer cells are comprised of two distinct clones, where one expresses a unique archetype. Over time, we found that the cells of this clone adapt by exhibiting a more similar profile to the corresponding archetype. |
| Key word |
melanoma; stress-like; single-cell RNA-seq; spatial transcriptomics; drug-resistant states; cancer cell states |
| Publication |
Baron, M. , et al. The Stress-Like Cancer Cell State Is a Consistent Component of Tumorigenesis. Cell Systems(2020). |
| Abstract |
Transcriptional profiling of tumors has revealed a stress-like state among the cancer cells with the concerted expression of genes such as fos, jun, and heat-shock proteins, though this has been controversial given possible dissociation-effects associated with single-cell RNA sequencing. Here, we validate the existence of this state using a combination of zebrafish melanoma modeling, spatial transcriptomics, and human samples. We found that the stress-like subpopulation of cancer cells is present from the early stages of tumorigenesis. Comparing with previously reported single-cell RNA sequencing datasets from diverse cancer types, including triple-negative breast cancer, oligodendroglioma, and pancreatic adenocarcinoma, indicated the conservation of this state during tumorigenesis. We also provide evidence that this state has higher tumor-seeding capabilities and that its induction leads to increased growth under both MEK and BRAF inhibitors. Collectively, our study supports the stress-like cells as a cancer cell state expressing a coherent set of genes and exhibiting drug-resistance properties. |
