Elucidating the selectivity of mineral uptake and its cytotoxic effects on breast cancer cells

Calcium phosphate microcalcifications (MCs) appear in most early breast cancer lesions and correlate with aggressive tumors and a poorer prognosis. Hydroxyapatite (HA) is a key MC component that crystallizes in the tumor microenvironment. We recently showed that inhibiting HA crystallization and modifying the precipitated mineral influences cellular responses. Contrary to the common belief that HA induces tumorigenesis, our findings reveal that its effects on cancer behavior can vary: depending on the mineral properties, HA can either suppress or promote cancerous activity. Our preliminary results indicate that these mineral particles are selectively taken up by precancerous and cancerous cells, but not by normal cells from the same isogenic cell line series. Moreover, particle uptake is strongly influenced by the surface charge of the particles. However, the mechanisms by which these particles influence cancer behavior remain unclear. We hypothesize that in addition to uptake, the intracellular processes these particles undergo—such as potential dissolution within or outside organelles and the formation of dense calcium condensates—play a significant role in the cellular response.
We propose to leverage a recent breakthrough in controlling particle uptake by adjusting their surface charge to investigate their intracellular interactions with organelles, spatial distribution, and dissolution dynamics. We aim to use cryo-SXT to image cells with varying malignancy potentials treated with amorphous and crystalline calcium phosphate particles of different surface charges. By employing spectro-microscopy, we will analyze the localization of intracellular particles and the concentration of ion-dense phases. This will advance our understanding of selective particle uptake by cancerous cells, shifting from descriptive observations to mechanistic insights into cellular processes. Since HA is not only associated with cancer but is also present in bones and teeth and commonly used as a biomaterial, insights from this research may enhance our understanding of cellular responses to HA in other tissues.