The SIX2/SOX2 axis is critical for promoting metastatic colonization of triple-negative breast cancer cells Survival Self-renewal Metastatic outgrowth Survival Self-renewal Metastatic outgrowth Survival Self-renewal Metastatic outgrowth The capacity for tumor cells to metastasize efficiently is directly linked to their ability to colonize secondary sites. Here we identify Six2, a developmental transcription factor, as a critical regulator of a breast cancer stem cell program that enables metastatic colonization. In several triple-negative breast cancer (TNBC) models, Six2 enhanced the expression of genes associated with embryonic stem cell programs. Six2 directly bound the Sox2 Srr2 enhancer, promoting Sox2 expression and downstream expression of Nanog, which are both key pluripotency factors. Regulation of Sox2 by Six2 enhanced cancer stem cell properties and increased metastatic colonization. Six2 and Sox2 expression correlated highly in breast cancers including TNBC, where a Six2 expression signature was predictive of metastatic burden and poor clinical outcome. Our findings demonstrate that a SIX2/SOX2 axis is required for efficient metastatic colonization, underscoring a key role for stemness factors in outgrowth at secondary sites. Significance: These findings provide novel mechanistic insight into stemness and the metastatic outgrowth of triple-negative breast cancer cells.

Constituting the bulk of rare-earth elements, lanthanides need to be separated to fully realize their potential as critical materials in many important technologies. The discovery of new ligands for improving rare-earth separations by solvent extraction, the most practical rare-earth separation process, is still largely based on trial and error, a low-throughput and inefficient approach. A predictive model that allows high-throughput screening of ligands is needed to identify suitable ligands to achieve enhanced separation performance. Here, we show that deep neural networks, trained on the available experimental data, can be used to predict accurate distribution coefficients for solvent extraction of lanthanide ions, thereby opening the door to high-throughput screening of ligands for rare-earth separations. One innovative approach that we employed is a combined representation of ligands with both molecular physicochemical descriptors and atomic extended-connectivity fingerprints, which greatly boosts the accuracy of the trained model. More importantly, we synthesized four new ligands and found that the predicted distribution coefficients from our trained machine-learning model match well with the measured values. Therefore, our machine-learning approach paves the way for accelerating the discovery of new ligands for rare-earth separations.

Lanthanide ion (LnIII) complexes with two new 1,8-naphthalimide-based ligands, Nap-dpe and Nap-cbx, were isolated, and their photophysical properties were explored. Upon excitation at 335 nm, Nap-dpe and Nap-cbx sensitize visible and near-infrared emitting LnIII ions (LnIII = EuIII, NdIII, and YbIII) and generate singlet oxygen (1O2). The quantum yields of EuIII luminescence for [Eu­(Nap-cbx)3]3+ and [Eu­(Nap-dpe)3]3+ are 16.7% and 8.3%, respectively, with 1O2 generation efficiencies of 41% and 59%, respectively. The efficiencies of 1O2 generation for the NIR emitting complexes [Ln­(Nap-dpe)3]3+ are 59% and 56%, respectively, and those for [Ln­(Nap-cbx)3]3+ (LnIII = NdIII, YbIII) are 64% and 61%, respectively. In an oxygen-free environment, the quantum yields of EuIII luminescence for [Eu­(Nap-cbx)3]3+ and [Eu­(Nap-dpe)3]3+ increase to 20% and 18%, respectively.

Separating rare earth elements is a daunting task due to their similar properties. We report a “tug of war” strategy that employs a lipophilic and hydrophilic ligand with contrasting selectivity, resulting in a magnified separation of target rare earth elements. Specifically, a novel water-soluble bis-lactam-1,10-phenanthroline with an affinity for light lanthanides is coupled with oil-soluble diglycolamide that selectively binds heavy lanthanides. This two-ligand strategy yields a quantitative separation of the lightest (e.g., La–Nd) and heaviest (e.g., Ho–Lu) lanthanides, enabling efficient separation of neighboring lanthanides in-between (e.g., Sm–Dy).

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