Modeling the role and regulation of reactive stroma in breast ductal carcinoma microinvasions

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous group of neoplastic lesions confined to the mammary ducts. Reactive stroma emerges during early breast cancer development and co-evolves with breast cancer progression. While genetic alterations during breast carcinogenesis have been extensively studied, more in-depth investigation is needed into the non-genetic microenvironmental factors that select for these genotypes. We hypothesize that emergence of reactive stroma precedes initiation of microinvasion, and that this process is an effect of a modified tissue metabolic landscape. This hypothesis will be tested using the interdisciplinary approach by explicitly integrating experimental and computational models that together are able to handle this problem complexity. We have assembled a multidisciplinary team of investigators to quantify tumor cell-stroma interactions under different metabolic conditions (aim 1); assess the role of reactive stroma in DCIS upgrading (aim 2); and evaluate reactive stroma signatures in DCIS histology (aim 3). We will pursue these aims by using a comprehensive approach that combines studies of DCIS histology samples, three-dimensional (3D) tumor organoid cultures, mathematical modeling of complex tumor microenvironment, and quantitative algorithms applied to medical imaging. Our goal is to define novel molecular and physical signatures of reactive stoma with a goal to improve preventive and therapeutic strategies.