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Single-cell analysis of tumor progression reveals the function, structure, and evolution of cancer archetypes

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE115140 | GEO | 2020/09/09

REPOSITORIES: GEO

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Project description:The optimal T cell attributes for the adoptive immunotherapy of cancer and viral diseases are currently unclear. Recent adoptive transfer clinical trials using ex vivo expanded tumor infiltrating lymphocytes has provided evidence that differentiated effector T cells can mediate durable responses in selected cancer patients. The capacity of these transferred cells to persist in the host was found to strongly correlate with their clinical activity. Thus, there is significant interest in identifying intrinsic markers that define antigen specific effector T cells that can develop into long-lived memory cells rather than undergoing apoptosis after infusion in humans. We recently reported the long term persistence of ex vivo expanded tumor specific CD8+ T effector clones in refractory metastatic melanoma patients after adoptive T cell transfer. By utilizing these highly homogeneous clone populations, we sought to define the pre-infusion cellular and molecular attributes associated with their effector to memory transition. Comparative transcriptional profiling found the pre-infusion clone mRNA expression levels of the IL-7 receptor (IL-7Ra) and the proto-oncogene, c-myc, directly correlated with the level of clonal persistence after adoptive transfer in humans. The predictive value of these markers was further established by utilizing IL-7R protein, induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor specific effector clones that could engraft after controlled adoptive transfer into highly immunodeficient mice. These findings support that IL-7R and c-myc expression are valuable cell intrinsic markers that can predict the fate of effector CD8+ T cells after adoptive transfer. We used microarrays to compare the pre-infusion gene expression profile of melanoma-specific CD8+ T cell clones that would eventually either persist or not after adoptive transfer in humans. We derived ten melanoma-specific CD8+ T cell clones and determined their degree of persistence after adoptive therapy into patients. We performed microarray on the pre-infusion samples of six persisting and four non-persisting clones to obtain a comparative gene signature profile.

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Single-cell analysis of tumor progression reveals the function, structure, and evolution of cancer archetypes

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