Spatiotemporal profiling defines persistence and resistance dynamics during targeted treatment of melanoma.

bioRxiv : the preprint server for biology(2024)

引用 0|浏览1
暂无评分
摘要
Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. Using spatial transcriptomics in patient derived xenograft models, we capture clonal lineage evolution during treatment, finding the persister state to show increased oxidative phosphorylation, decreased proliferation, and increased invasive capacity, with central-to-peripheral gradients. Phylogenetic tracing identifies intrinsic- and acquired-resistance mechanisms (e.g. dual specific phosphatases, Reticulon-4, CDK2) and suggests specific temporal windows of potential therapeutic efficacy. Using deep learning to analyze histopathological slides, we find morphological features of specific cell states, demonstrating that juxtaposition of transcriptomics and histology data enables identification of phenotypically-distinct populations using imaging data alone. In summary, we define state change and lineage selection during melanoma treatment with spatiotemporal resolution, elucidating how choice and timing of therapeutic agents will impact the ability to eradicate resistant clones. Statement of Significance:Tumor evolution is accelerated by application of anti-cancer therapy, resulting in clonal expansions leading to dormancy and subsequently resistance, but the dynamics of this process are incompletely understood. Tracking clonal progression during treatment, we identify conserved, global transcriptional changes and local clone-clone and spatial patterns underlying the emergence of resistance.
更多
查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要