Engineered mineralized hydrogels to study microcalcifications in breast cancer

Engineered mineralized hydrogels to study microcalcifications in breast cancer ABSTRACT Breast cancer (BrCa) remains a significant global challenge, with recurrence and metastasis posing critical obstacles to improving patient survival. Unfortunately, treatments that effectively eliminate metastasis are lacking, emphasizing the urgent need for early interventions to prevent BrCa progression. Such interventions can only be developed by understanding the primary tumor microenvironment (TME) and its role in influencing BrCa cells to initiate metastatic programs. This proposal aims to investigate potential risk factors and early mechanisms within the primary TME that predispose tumor cells (the "seed") to metastasize. One such factor is mammographic microcalcifications (MCs)- insoluble calcium deposits that aid in detecting over half of nonpalpable BrCa cases and 70-90% of pre-invasive BrCa cases. Type I MCs (calcium oxalate, OX) are observed in benign breast conditions, whereas Type II MCs (calcium phosphate, hydroxyapatite (HA)) are primarily associated with malignant disease. Despite their diagnostic value, the influence of the chemical composition of MCs in shaping the primary TME and BrCa progression remains unexamined mainly due to the lack of suitable experimental systems that accurately reflect the chemical composition of MCs within the primary breast TME. To address this gap, we have developed a novel, patented extracellular matrix hydrogels (ECM-mimics) that recapitulate the soft breast TME, and the distinct MC compositions observed in MC-positive BrCa —an otherwise difficult feature to study in vivo. Our study will evaluate how MCs, particularly their chemical composition, may contribute to aggressive tumor growth, bone mimicry, and metastatic BrCa progression. Aim 1 tests the hypothesis that malignant MCs promote tumor growth and bone mimicry in the primary TME through Na-Pi transporter signaling. In Aim 2, we test the hypothesis that the interactions of breast cancer cells with malignant MCs facilitate breast-to-bone metastasis through the acquisition of bone mimicry. In both aims, we test novel molecular mechanisms underlying the currently unknown role of malignant MC-mediated BrCa progression using in vitro, ex vivo, and in vivo CDX and PDX models and validate our findings in patient samples with and without MCs. Together, the successful completion of this project will provide valuable insights into the mechanisms underlying effects of the mineralized TME on BrCa progression, identify novel biomarkers to stratify high-risk patients, and inform local therapeutic interventions such as bisphosphonates, denosumab, and phosphate transporter inhibitors to block this metastatic cascade for those at risk. Project Number: 1R01CA304933-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Shilpa Sant | Institution: UNIVERSITY OF ILLINOIS AT CHICAGO, Chicago, IL | Award Amount: $565,909 | Activity Code: R01 | Study Section: Tumor Host Interactions Study Section[THI] View on NIH RePORTER: https://reporter.nih.gov/project-details/11366460