@article{923cb77e4b1047e583175b44782a66ff,
title = "Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma",
abstract = "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, MIBI, breast cancer, myoepithelium, spatial proteomics, systems biology, tumor microenvironment, tumor progression",
author = "Tyler Risom and Glass, {David R.} and Inna Averbukh and Liu, {Candace C.} and Alex Baranski and Adam Kagel and McCaffrey, {Erin F.} and Greenwald, {Noah F.} and Bel{\'e}n Rivero-Guti{\'e}rrez and Strand, {Siri H.} and Sushama Varma and Alex Kong and Leeat Keren and Sucheta Srivastava and Chunfang Zhu and Zumana Khair and Veis, {Deborah J.} and Katherine Deschryver and Sujay Vennam and Carlo Maley and Hwang, {E. Shelley} and Marks, {Jeffrey R.} and Bendall, {Sean C.} and Colditz, {Graham A.} and West, {Robert B.} and Michael Angelo",
note = "Funding Information: This publication is part of the HTAN (Human Tumor Atlas Network) Consortium paper package. A list of HTAN members is available at humantumoratlas.org/htan-authors/. The authors thank the HTAN Consortium for intellectual and collaborative support of this work. We thank Pauline Chu and the Stanford Human Histology Core for providing technical assistance. T.R. was supported by American Cancer Society Postdoctoral Fellowship 133099-PF-19-002-01-CCE and Stanford Immunology Training Grant 5 T32 AI07290-33 . D.R.G. was supported by the Bio-X Stanford Interdisciplinary Graduate Fellowship. C.C.L. was supported by the Stanford Graduate Fellowship. E.S.H. is funded by RFA-CA-17-035 ( NIH ), 1505-30497 ( PCORI ), and BCRF 19-074 ( BCRF ); E.S.H. and C.M. are funded by DOD BC132057 and R01 CA185138-01 . R.B.W. was supported by R01CA193694 and U2C CA233254 . M.A. was supported by 1-DP5-OD019822 . S.C.B. and M.A. were jointly supported by 1R01AG056287 , 1R01AG057915 , 1U24CA224309 , the Bill and Melinda Gates Foundation , and a Translational Research Award from the Stanford Cancer Institute . Graphical abstract was created with Biorender.com . Funding Information: This publication is part of the HTAN (Human Tumor Atlas Network) Consortium paper package. A list of HTAN members is available at humantumoratlas.org/htan-authors/. The authors thank the HTAN Consortium for intellectual and collaborative support of this work. We thank Pauline Chu and the Stanford Human Histology Core for providing technical assistance. T.R. was supported by American Cancer Society Postdoctoral Fellowship 133099-PF-19-002-01-CCE and Stanford Immunology Training Grant 5 T32 AI07290-33. D.R.G. was supported by the Bio-X Stanford Interdisciplinary Graduate Fellowship. C.C.L. was supported by the Stanford Graduate Fellowship. E.S.H. is funded by RFA-CA-17-035 (NIH), 1505-30497 (PCORI), and BCRF 19-074 (BCRF); E.S.H. and C.M. are funded by DOD BC132057 and R01 CA185138-01. R.B.W. was supported by R01CA193694 and U2C CA233254. M.A. was supported by 1-DP5-OD019822. S.C.B. and M.A. were jointly supported by 1R01AG056287, 1R01AG057915, 1U24CA224309, the Bill and Melinda Gates Foundation, and a Translational Research Award from the Stanford Cancer Institute. Graphical abstract was created with Biorender.com. T.R. conceived the study design, performed experiments, analyzed data, and wrote the manuscript with M.A. D.R.G. developed the classifier model and performed related analyses. C.C.L. developed the myoepithelial pixel-clustering approach and performed related analyses. I.A. assisted with tissue feature comparison and developed the LDA model. S.H.S. processed the LCM-RNA-seq data, and B.R-G. performed all RNA-seq analyses. E.F.M. assisted with data analysis with A. Kong, L.K. and S. Vennam. N.F.G. assisted with image segmentation. A.B. developed and performed the myoepithelial morphology analyses, and A. Kagel performed the collagen morphology analyses. G.A.C. D.J.V. and K.D. assisted with cohort design and patient sample preparation. S.S. performed pathology reviews. S. Varma and Z.K. assisted with immunohistochemistry. E.S.H. S.C.B. R.B.W. and M.A. supervised the work. M.A. and S.C.B. are inventors on patent US20150287578A1. M.A. and S.C.B. are board members and shareholders in IonPath Inc. T.R. and E.F.M. have previously consulted for IonPath Inc. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = jan,
day = "20",
doi = "10.1016/j.cell.2021.12.023",
language = "English",
volume = "185",
pages = "299--310.e18",
journal = "Cell",
issn = "0092-8674",
number = "2",
}