Friday, May 9, 2025
5/9/2025
Tumor microenvironmental biomarkers of breast cancer invasion - Project Summary Ductal carcinoma is the most common form of breast cancer, yet it remains unclear how the neoplasia makes the transition from the pre-invasive stage (ductal carcinoma in situ or DCIS) to invasive breast cancer (IBC). This transition cannot be explained by genetic changes, thereby implicating the tumor microenvironment (TME), including changes in extracellular matrix (ECM) structure and mechanics, and altered activity of fibroblasts and macrophages. However, the mechanistic role of these factors have been difficult to examine because human patient analyses are largely correlative in nature, and the lack of tunable animal models of human DCIS. In this R01 proposal, we take an innovative approach that utilizes in vivo analyses to identify all features that are correlated with the invasive transition, in vitro studies to determine which of these features are causal for the transition, and then in vivo data with patient cohorts to examine how these causal features improve predictors for outcome. The overall hypothesis guiding this work is that a synergistic combination of changes in ECM structure and mechanics, macrophage and fibroblast signaling regulate invasion. Preliminary work from our Pre- cancer Atlas has discovered pathways and biology that are correlated with progression, including a desmoplastic stromal signature, collagen fiber architecture, and trafficking of monocytes and macrophages. Preliminary work from our 3D culture model of pre-invasive breast cancer shows that the model captures key features of human DCIS, identified increased ECM stiffness as a key causal driver of invasion, and identified molecular mechanisms underlying the impact of stiffness on the invasive transition. In Aim 1, our in vivo analysis will identify features of the DCIS cells and the collagen stroma that are spatially correlated with invasion, while in vitro and computational analysis will use a 3D culture model of pre-invasive breast cancer to identify which of those features are causal for invasion, with analysis of a longitudinal cohort then indicating which of these features predict outcome. In Aim 2, we will determine the driver role of macrophage and fibroblast activity on the DCIS to IBC transition. In vivo analysis will identify features of the macrophages and fibroblasts that are spatially correlated with invasion, while in vitro analysis will identify which of these features are causal drivers of invasion andanalysis of a longitudinal cohort then indicating which of these features predict outcome. In Aim 3, we will examine the predictive power of these features. Innovative features of this proposal include the innovative design that integrates in vivo, in vitro, and in silico analysis. Significant clinically relevant outcomes of the work include: (1) Improved estimation of the likelihood that the DCIS is aggressive and will progress if left untreated and (2) Determination of the probability of the presence of “occult” invasive cancer that was not sampled by the core biopsy procedure.
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