美国加州大学Trever G. Bivona、Collin M. Blakely和美国Chan Zuckerberg Biohub公司Spyros Darmanis课题组合作取得一项新突破。他们利用单细胞RNA测序揭示了治疗诱导的人肺癌进化过程。该项研究成果在线发表在2020年8月20日的《细胞》上。
研究人员对30例患者靶向治疗前和治疗过程中获得的49份临床活检样品进行了转移性肺癌单细胞RNA测序（scRNA-seq）。超过20,000个癌症和肿瘤微环境（TME）单细胞分布图揭示了丰富而动态的肿瘤生态系统。癌细胞scRNA-seq揭示了可靶向的癌基因，这超出了临床上检测到的靶基因。
残留病变（RD）存活下来的癌细胞表达肺泡再生的细胞标志物，表明治疗诱导了原始细胞状态的转变，而治疗上存在疾病进展（PD）的癌细胞则上调了犬尿氨酸、纤溶酶原和间隙连接通路。在RD处存在激活T淋巴细胞和巨噬细胞的减少，以PD为特征的细胞免疫抑制状态。由scRNA-seq揭示的生物学特征独立于临床上观察到的生物标志物。这项研究突出了治疗诱导的转移性癌症多细胞生态环境适应性如何影响临床治疗效果。
据悉，肺癌是导致癌症死亡的主要癌症之一，它具有异质性、可适应性强的特点，这限制了其治疗，并且仍存在许多未解问题。
附：英文原文
Title: Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing
Author: Ashley Maynard, Caroline E. McCoach, Julia K. Rotow, Lincoln Harris, Franziska Haderk, D. Lucas Kerr, Elizabeth A. Yu, Erin L. Schenk, Weilun Tan, Alexander Zee, Michelle Tan, Philippe Gui, Tasha Lea, Wei Wu, Anatoly Urisman, Kirk Jones, Rene Sit, Pallav K. Kolli, Eric Seeley, Yaron Gesthalter, Daniel D. Le, Kevin A. Yamauchi, David M. Naeger, Sourav Bandyopadhyay, Khyati Shah, Lauren Cech, Nicholas J. Thomas, Anshal Gupta, Mayra Gonzalez, Hien Do, Lisa Tan, Bianca Bacaltos, Rafael Gomez-Sjoberg, Matthew Gubens, Thierry Jahan, Johannes R. Kratz, David Jablons, Norma Neff, Robert C. Doebele, Jonathan Weissman, Collin M. Blakely, Spyros Darmanis, Trever G. Bivona
Issue&Volume: 2020-08-20
Abstract: Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enablesadaptability, limits therapeutic success, and remains incompletely understood. Single-cellRNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinicalbiopsies obtained from 30 patients before and during targeted therapy. Over 20,000cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamictumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyondthose detected clinically. Cancer cells surviving therapy as residual disease (RD)expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitivecell-state transition, whereas those present at on-therapy progressive disease (PD)upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytesand decreased macrophages were present at RD and immunosuppressive cell states characterizedPD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomesin independent cohorts. This study highlights how therapy-induced adaptation of themulti-cellular ecosystem of metastatic cancer shapes clinical outcomes.
DOI: 10.1016/j.cell.2020.07.017
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30882-5