Summary
Mechanisms of therapeutic resistance manifest in metastatic cancers as tumor cell intrinsic alterations and extrinsic microenvironmental influences that can change during treatment. To support the development of methods for the identification of these mechanisms in individual patients, we present here an Omic and Multidimensional Spatial (OMS) Atlas generated from four serial biopsies of a metastatic breast cancer patient during 3.5 years of therapy. This resource links detailed, longitudinal clinical metadata including treatment times and doses, anatomic imaging, and blood-based response measurements to exploratory analytics including comprehensive DNA, RNA, and protein profiles, images of multiplexed immunostaining, and 2- and 3-dimensional scanning electron micrographs. These data reveal aspects of therapy-associated heterogeneity and evolution of the cancer’s genome, signaling pathways, immune microenvironment, cellular composition and organization, and ultrastructure. We present illustrative examples showing how integrative analyses of these data provide insights into potential mechanisms of response and resistance, and suggest novel therapeutic vulnerabilities.
Competing Interest Statement
D.S. is employed by Quantitative Imaging Systems, which sells image analysis software. L.M.C. is a paid consultant for Cell Signaling Technologies, Shasqi Inc., and AbbVie Inc.; received reagent and/or research support from Plexxikon Inc., Pharmacyclics Inc., Acerta Pharma, LLC, Deciphera Pharmaceuticals, LLC, Genentech Inc., Roche Glycart AG, Syndax Pharmaceuticals Inc., Innate Pharma, and NanoString Technologies; and is a member of the Scientific Advisory Boards of Syndax Pharmaceuticals, Carisma Therapeutics, Zymeworks Inc., Verseau Therapeutics, Cytomix Therapeutics Inc., and Kineta Inc. G.B.M. has licensed technologies to Myriad Genetics and Nanostring; is on the SAB or is a consultant to Amphista, AstraZeneca, Chrysallis Biotechnology, GSK, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda, Turbine, and Zentalis Pharmaceuticals; and has stock/options/financial interests in Catena Pharmaceuticals, ImmunoMet, SignalChem, and Tarveda. J.W.G. has licensed technologies to Abbott Diagnostics; has ownership positions in Convergent Genomics, Health Technology Innovations, Zorro Bio, and PDX Pharmaceuticals; serves as a paid consultant to New Leaf Ventures; has received research support from Thermo Fisher Scientific (formerly FEI), Zeiss, Miltenyi Biotech, Quantitative Imaging, Health Technology Innovations, and Micron Technologies; and owns stock in Abbott Diagnostics, AbbVie, Alphabet, Amazon, Amgen, Apple, General Electric, Gilead, Intel, Microsoft, Nvidia, and Zimmer Biomet.
Footnotes
Author List Footnotes: Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Joe Gray (grayjo{at}ohsu.edu).
Text revision to present the data as an atlas; Text, Figures 2-6, Figures S1-S6, Tables S1-S2 revised to include new data; additional authors added.
