Cancer cells form three dimensional (3D) multicellular aggregates (or
spheroids) under non-adherent culture conditions. In ovarian cancer (OC),
spheroids serve as a vehicle for cancer cell dissemination in the peritoneal
cavity, protecting cells from environmental stress-induced anoikis. To identify
new targetable molecules in OC spheroids, we investigated gene expression
profiles and networks upregulated in three dimensional (3D) versus traditional
monolayer culture conditions. We identified ALDH1A1, a cancer
stem cell marker as being overexpressed in OC spheroids and directly connected
to key elements of the β-catenin pathway. B-catenin function and
ALDH1A1 expression were increased in OC spheroids vs.
monolayers and in successive spheroid generations, suggesting that 3D aggregates
are enriched in cells with stem cell characteristics. B-catenin knockdown
decreased ALDH1A1 expression levels and β-catenin
coimmunoprecipitated with the ALDH1A1 promoter, suggesting that
ALDH1A1 is a direct β-catenin target. Both siRNA
mediated β-catenin knockdown and A37, a novel ALDH1A1 small molecule
enzymatic inhibitor described here for the first time, disrupted OC spheroid
formation and cell viability (p<0.001). B-catenin knockdown blocked tumor
growth and peritoneal metastasis in an OC xenograft model. These data strongly
support the role of β-catenin regulated ALDH1A1 in the maintenance of OC
spheroids and propose new ALDH1A1 inhibitors targeting this cell population.
Microscopic imaging of cellular motility has recently advanced from two dimensions to three dimensions for applications in drug development. However, significant degradation in resolution occurs with increasing imaging depth, limiting access to motility information from deep inside the sample. Here, digital holographic optical coherence imaging is adapted to allow visualization of motility in tissue at depths inaccessible to conventional motility assay approaches. This method tracks the effect of cytoskeletal anti-cancer drugs on tissue inside its natural three-dimensional environment using time-course measurement of motility within tumor tissue.
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