Refining the Molecular Framework for Pancreatic Cancer with Single-cell and Spatial Technologies.
Refining the Molecular Framework for Pancreatic Cancer with Single-cell and Spatial Technologies.
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DOI：
10.1158/1078-0432.ccr-20-4712
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发表时间：
2021-07-15
期刊：
影响因子：
--
通讯作者：
Hwang WL
中科院分区：
文献类型：
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作者：
Guo JA;Hoffman HI;Weekes CD;Zheng L;Ting DT;Hwang WL
胰腺导管腺癌（PDAC）是一种治疗难治性恶性肿瘤，迫切需要一个分子框架来指导治疗策略。在过去的十年中，大量的转录组学研究已经产生了两种广泛的共识亚型：经典胰腺/上皮与基底样/鳞状/准间充质。虽然这种二元分类能够进行预后分层，但目前并不能告知对任一亚型唯一敏感的治疗的施用。此外，批量mRNA研究面临的挑战是区分肿瘤区室与微环境中其他细胞类型的贡献，这在PDAC中尤为突出，因为肿瘤细胞可能较低。单细胞转录组学在胰腺肿瘤中的应用通常落后于其他癌症类型，部分原因是难以从酶降解组织中提取高质量的RNA，但新兴的研究已经并将继续揭示肿瘤内异质性，恶性基质相互作用以及以前在批量水平上模糊的微妙转录程序。结合单细胞/细胞核解离技术提供的见解，空间分辨技术还应促进肿瘤结构内基因程序和推断的细胞-细胞相互作用的情境化。最后，考虑到患者经常接受新辅助化疗和/或放化疗，即使在可切除的疾病，破译基因程序丰富或诱导细胞毒性治疗将是至关重要的发展见解，旨在消除残留的癌细胞的补充治疗。总之，单细胞和空间技术提供了一个前所未有的机会，可以完善先前大量分子研究奠定的基础，并显着增强胰腺癌的精确肿瘤学工作。
Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy in urgent need of a molecular framework for guiding therapeutic strategies. Bulk transcriptomic efforts over the past decade have yielded two broad consensus subtypes: classical-pancreatic/epithelial versus basal-like/squamous/quasi-mesenchymal. While this binary classification enables prognostic stratification, it does not currently inform the administration of treatments uniquely sensitive to either subtype. Furthermore, bulk mRNA studies are challenged by distinguishing contributions from the neoplastic compartment versus other cell types in the microenvironment, which is accentuated in PDAC given that neoplastic cellularity can be low. The application of single-cell transcriptomics to pancreatic tumors has generally lagged behind other cancer types due in part to the difficulty of extracting high-quality RNA from enzymatically-degradative tissue, but emerging studies have and will continue to shed light on intra-tumoral heterogeneity, malignant-stromal interactions, and subtle transcriptional programs previously obscured at the bulk level. In conjunction with insights provided by single-cell/nucleus dissociative techniques, spatially resolved technologies should also facilitate the contextualization of gene programs and inferred cell-cell interactions within the tumor architecture. Finally, given that patients often receive neoadjuvant chemotherapy and/or chemoradiotherapy even in resectable disease, deciphering the gene programs enriched in or induced by cytotoxic therapy will be crucial for developing insights into complementary treatments aimed at eradicating residual cancer cells. Taken together, single-cell and spatial technologies provide an unprecedented opportunity to refine the foundations laid by prior bulk molecular studies and significantly augment precision oncology efforts in pancreatic cancer.