Growth directions and stiffness across cell layers determine whether tissues stay smooth or buckle.

From smooth to buckled, nature exhibits organs of various shapes and forms. How cellular growth patterns produce smooth organ shapes such as leaves and sepals remains unclear. Here we show that unidirectional growth and comparable stiffness across both epidermal layers of Arabidopsis sepals are essential for smoothness. We identified a mutant with ectopic ASYMMETRIC LEAVES 2 (AS2) expression on the outer epidermis. Our analysis reveals that ectopic AS2 expression causes outer epidermal buckling at early stages of sepal development, due to conflicting growth directions and unequal epidermal stiffnesses. Aligning growth direction and increasing stiffness of the outer epidermis restores smoothness. Furthermore, buckling influences auxin efflux transporter protein PIN-FORMED 1 polarity to generate outgrowth in the later stages, suggesting that buckling is sufficient to initiate outgrowths. Our findings suggest that in addition to molecular cues influencing tissue mechanics, tissue mechanics can also modulate molecular signals, giving rise to well-defined shapes.

Targeting Cancer Stem Cells with Differentiation Agents as an Alternative to Genotoxic Chemotherapy for the Treatment of Malignant Testicular Germ Cell Tumors.

Testicular germ cell tumors (TGCTs) are exceptionally sensitive to genotoxic chemotherapy, resulting in a high cure rate for the young men presenting with these malignancies. However, this treatment is associated with significant toxicity, and a subset of malignant TGCTs demonstrate chemoresistance. Mixed nonseminomas often contain pluripotent embryonal carcinoma (EC) cells, the cancer stem cells (CSCs) of these tumors. We hypothesized that differentiation therapy, a treatment strategy which aims to induce differentiation of tumor-propagating CSCs to slow tumor growth, could effectively treat mixed nonseminomas without significant toxicity. The FDA-approved antipsychotic thioridazine and the agricultural antibiotic salinomycin are two drugs previously found to selectively target CSCs, and here we report that these agents differentiate EC cells in vitro and greatly reduce their tumorigenic potential in vivo. Using a novel transformed induced pluripotent stem cell allograft model and a human xenograft model, we show that thioridazine extends the survival of tumor-bearing mice and can reduce the number of pluripotent EC cells within tumors. These results suggest that thioridazine could be repurposed as an alternative TGCT treatment that avoids the toxicity of conventional chemotherapeutics.