(282g) Invited Speaker: Engineered Microenvironments to Study Breast Cancer Progression

Women do not die of breast cancer confined to the breast and the draining lymph node; instead an estimated 90% of breast cancer deaths are due to metastasis to a distant organ. Approximately 20% of breast cancers detected through mammography are preinvasive Ductal Carcinoma in situ (DCIS). If left untreated, approximately 20-50% of DCIS will progress to Invasive Ductal Carcinoma (IDC) with high mortality. The factors contributing to the transition from pre-invasive to invasive disease remain unknown leading to overtreatment of patients that are not at risk. Three-dimensional (3D) in vitro microenvironments can recapitulate the major hallmarks of DCIS-IDC progression, which include hypoxic microenvironments and microcalcifications (MCs) to elucidate the underlying mechanisms. We use hydrogel-based materials to engineer these hallmarks and elucidate the effect of microenvironmental factors on breast cancer progression. We have utilized our microfabricated hydrogel microwells to generate uniform, discretesized,
3D organoids with controlled microenvironments using a variety of cancer cell lines and primary patient-derived cells. Without any external stimulus, large organoids develop three key hallmarks of DCIS observed in vivo: increasing organoid size drives hypoxia and metabolic stress; heterogeneous tumor cells spontaneously emerge; and peripheral cells begin to migrate from the parent tumor. A tangible advantage of size controlled microwells is the ability to precisely and reproducibly study how the hypoxic microenvironment induces tumor migration in real time in the same cell population and in isolation from non-tumor cells present in vivo, providing unique opportunity to define tumor-intrinsic mechanisms of transition from non-invasive to invasive phenotypes.

In another study, we have developed collagen-mimetic hydrogels and engineered in vitro microenvironments to study role of benign calcium oxalate vs. malignant hydroxyapatitelike microcalcifications (MCs) in non-invasive to invasive disease progression. A tangible advantage of collagen-mimetic hydrogels is precise control over composition of benign oxalate-like and malignant hydroxyapatite-like MCs. We have shown that our model can
recapitulate clinically observed induction of invasive as well as bone-like phenotypes in non-invasive human DCIS and IDC cells.

Overall, engineered controlled microenvironments can advance our knowledge of various microenvironmental factors such as hypoxic tumor secretome or MCs in breast cancer progression.