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乳腺导管原位癌是一种浸润前病变，其肿瘤细胞被肌上皮和基底膜蛋白质层与周围基质隔开，被认为是乳腺浸润癌的前兆，大约占新诊断乳腺癌的20%。乳腺导管原位癌与乳腺浸润癌相比，本身并不威胁生命。不过，如果不及时治疗，将近一半的乳腺导管原位癌在10年内可进展为乳腺浸润癌。由于这种不确定性，临床医师倾向于将全部乳腺导管原位癌患者认定为乳腺浸润癌进展者，通过手术、放疗和药物进行干预，而这些方法都存在不良反应的风险，对于未进展患者，这些方法可能过于激进。因此，了解究竟是什么促使乳腺导管原位癌进展为乳腺浸润癌，将有助于早期预防或者避免不必要的过度治疗。 2022年1月20日，全球自然科学三大旗舰期刊之一、美国《细胞》正刊发表斯坦福大学、基因泰克、圣路易斯华盛顿大学、杜克大学、亚利桑那州立大学的人类肿瘤图谱协作组研究报告，探讨了伴随乳腺导管原位癌向乳腺浸润癌转变的肿瘤微环境变化。 
该研究采用多重离子束飞行时间成像技术、37组细胞蛋白质标志物金属缀合抗体染色、人工智能机器学习工具，对手术切除的9例正常乳腺组织、58例乳腺导管原位癌（其中进展者14例、未进展者44例）和12例乳腺浸润癌（其中9例进展自乳腺导管原位癌）临床标本进行细胞蛋白质标志物空间分布特征分类和形态分析。 
结果发现，正常乳腺组织与患者的乳腺导管原位癌和乳腺浸润癌相比，根据肌上皮、成纤维细胞和免疫细胞的空间分布和功能，存在四种肿瘤微环境状态之间的同步转变，乳腺导管原位癌微环境结构可预测诊断后10年内的浸润复发。 
令人惊讶的是，乳腺导管原位癌未进展为乳腺浸润癌患者的肌上皮破坏反而更严重，复发风险很大程度受到肌上皮表现型和形态学的影响，这表明该过程可能对复发具有预防作用。 
因此，该研究结果表明，乳腺导管原位癌向乳腺浸润癌的转变，与肿瘤微环境基质结构和组成的动态变化密切相关。这是全球首个乳腺浸润癌前空间分布特征图谱研究，首次明确了乳腺导管原位癌复发进展为乳腺浸润癌的组织转录组学驱动因素，并强调了肿瘤微环境对于调节这些过程的重要性。 Cell. 2022 Jan 20;185(2):299-310.e18.
Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma. Tyler Risom, David R. Glass, Inna Averbukh, Candace C. Liu, Alex Baranski, Adam Kagel, Erin F. McCaffrey, Noah F. Greenwald, Belén Rivero-Gutiérrez, Siri H. Strand, Sushama Varma, Alex Kong, Leeat Keren, Sucheta Srivastava, Chunfang Zhu, Zumana Khair, Deborah J. Veis, Katherine Deschryver, Sujay Vennam, Carlo Maley, E. Shelley Hwang, Jeffrey R. Marks, Sean C. Bendall, Graham A. Colditz, Robert B. West, Michael Angelo. Stanford University School of Medicine, Stanford, CA, USA; Genentech, South San Francisco, CA, USA; Washington University School of Medicine, St. Louis, MO, USA; Duke University, Durham, NC, USA; Arizona State University, Tempe, AZ, USA. HIGHLIGHTS A spatial atlas of breast cancer progression using MIBI-TOF and tissue transcriptomics Coordinated changes in the tumor microenvironment (TME) track invasive transition of DCIS DCIS TME structure is predictive of invasive relapse within 10 years of diagnosis Recurrence risk is heavily influenced by myoepithelial phenotype and morphology
Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune cells. Surprisingly, myoepithelial disruption was more advanced in DCIS patients that did not develop IBC, suggesting this process could be protective against recurrence. Taken together, this HTAN Breast PreCancer Atlas study offers insight into drivers of IBC relapse and emphasizes the importance of the TME in regulating these processes. KEYWORDS: DCIS, tumor microenvironment, MIBI, spatial proteomics, breast cancer, tumor progression, systems biology, myoepithelium DOI: 10.1016/j.cell.2021.12.023 
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