Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Institute for Biomedical Materials and Devices, University of Technology Sydney, Sydney, NSW 2007, Australia.
Cell Rep. 2021 Apr 13;35(2):108945. doi: 10.1016/j.celrep.2021.108945.
Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.
基底样乳腺癌与年轻、早期复发和高死亡率有关。在这里，我们使用无偏倚的基于液滴的单细胞 RNA 测序（RNA-seq）来阐明在 MMTV-PyMT（鼠乳腺肿瘤病毒-多瘤中肿瘤抗原）乳腺肿瘤模型中，从腔前体细胞群中特化基底样乳腺癌亚型过程中的肿瘤进展的细胞基础。我们发现基底样癌细胞类似于妊娠时特化的肺泡谱系，并包含获得异常的泌乳后退化发育程序，从而触发肿瘤微环境的重塑和转移扩散。这种退化模拟的特征是具有高度交互的多细胞网络，其中退化的癌相关成纤维细胞在细胞外基质重塑和免疫抑制中发挥关键作用。我们的结果可能部分解释了与生育相关的乳腺癌风险增加和预后不良的原因。
