Omic and Multidimensional Spatial Atlas of Metastatic Breast Cancer

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PROJECT ABSTRACT We will continue development of our Omic and Multidimensional Spatial (OMS) Atlas that enables discovery of mechanisms of resistance that arise in individual patients with metastatic breast cancer during treatment with current generation targeted therapeutic combinations and immune checkpoint inhibitors. The OMS Atlas is motivated by the fact that these treatments typically are only transiently effective in the metastatic setting. Possible resistance mechanisms may be intrinsic to the tumor cells or derive from the diverse microenvironments in which the tumor cells live. The OMS Atlas focuses on elucidating these resistance mechanisms in two current generation clinical scenarios: (a) hormone-receptor positive breast cancer (HRBC) undergoing treatment with a CDK4/6 inhibitor in combination with endocrine therapy, and (b) triple negative breast cancer (TNBC) undergoing treatment with a PARP inhibitor and an immunomodulatory agent. We are accomplishing this through work via four coordinated units. A Biospecimen Unit is prospectively collecting and distributing longitudinal clinical information, blood, and biopsies from 30 cases across the two metastatic breast cancer cohorts. A Characterization Unit is analyzing (a) OCT frozen specimens using single-cell DNA-seq and single-cell ATAC- seq to elucidate spatially defined genomic changes and chromatin accessibility in single cells, (b) formalin fixed, paraffin embedded (FFPE) specimens using multiplex immunohistochemistry (mIHC) to assess the immune microenvironment and cyclic Immunofluorescence (cycIF) to assess the composition and molecular states of tumor cells and their microenvironments, and (c) paraformaldehyde fixed, resin embedded (PFRE) specimens using a Focused Ion Beam Scanning Electron Microscope (FIB-SEM) to identify ultrastructural changes in 2D images and targeted 3D images. Omic characterization of the same tumor samples is provided by the SMMART Program. A Data Analysis Unit is developing and deploying tools to (a) manage, analyze, and visualize omics and imaging datasets, (b) integrate omics and imaging datasets through crosswise mapping to create single timepoint tumor maps and quantify systems biological functions of tumor cellular subpopulations, and (c) explore differences between pre- and on/post-treatment tumor maps to reveal mechanisms of resistance. The Administrative Unit facilitates the coordination, operation, interaction, and evaluation of activities within the OMS Atlas and between OMS Atlas scientists and the HTAN. In this project, we will complete our planned OMS Atlas project through the following Aims: (1) perform characterization of five additional patient cases using our omics and multiscale imaging assays; (2) upload our remaining datasets and metadata to the HTAN data coordinating center; and (3) perform integrated data analysis across our atlas case datasets as well as HTAN trans-network project datasets to identify tumor changes on therapy and the implications of those changes on breast cancer treatment. By accomplishing these aims we will complete and fully share our multimodal spatial atlas of 30 metastatic breast cancer cases undergoing treatment.