Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes.

Loss of TP53 and RB1 in treatment-naïve small cell lung cancer (SCLC) suggests selective pressure to inactivate cell death pathways prior to therapy. Yet, which of these pathways remain available in treatment-naïve SCLC is unknown. Here, through systemic analysis of cell death pathway availability in treatment-naïve SCLC, we identify non-neuroendocrine (NE) SCLC to be vulnerable to ferroptosis through subtype-specific lipidome remodeling. While NE SCLC is ferroptosis resistant, it acquires selective addiction to the TRX anti-oxidant pathway. In experimental settings of non-NE/NE intratumoral heterogeneity, non-NE or NE populations are selectively depleted by ferroptosis or TRX pathway inhibition, respectively. Preventing subtype plasticity observed under single pathway targeting, combined treatment kills established non-NE and NE tumors in xenografts, genetically engineered mouse models of SCLC and patient-derived cells, and identifies a patient subset with drastically improved overall survival. These findings reveal cell death pathway mining as a means to identify rational combination therapies for SCLC.

Highly expressed placental miRNAs control key biological processes in human cancer cell lines.

Despite being a healthy tissue, the constituent cells of the placenta, share similar characteristics with tumor cells, such as increased cell growth, migration, and invasion. However, while these processes are stochastic and uncontrolled in cancer cells, in placenta they are precisely controlled. Since miRNAs have been reported to regulate genes that control the molecular mechanisms necessary for the development of both human placenta and cancer, we addressed for miRNAs highly expressed in the placenta that could be involved in tumorigenesis. Here, we assessed the miRNA profile in placenta samples using microarray analysis. The results showed that miR-451 and miR-720, highly expressed placental miRNAs, presented very low or undetectable expression in cancer cell lines compared to the normal placenta and healthy tissues. Additionally, transfection of miR-451 or miR-720 mimics in choriocarcinoma cell line (JEG3) and colorectal adenocarcinoma cell line (HT-29) resulted in impaired cell proliferation, decreased cell migration and invasion and reduced ability of colony formation. These findings provide evidence that placenta may work as an alternative model to identify novel miRNAs involved in pathways controlling tumorigenesis.

Brief report: The lincRNA Hotair is required for epithelial-to-mesenchymal transition and stemness maintenance of cancer cell lines.

Hotair is a member of the recently described class of noncoding RNAs called lincRNA (large intergenic noncoding RNA). Various studies suggest that Hotair acts regulating epigenetic states by recruiting chromatin-modifying complexes to specific target sequences that ultimately leads to suppression of several genes. Although Hotair has been associated with metastasis and poor prognosis in different tumor types, a deep characterization of its functions in cancer is still needed. Here, we investigated the role of Hotair in the scenario of epithelial-to-mesenchymal transition (EMT) and in the arising and maintenance of cancer stem cells (CSCs). We found that treatment with TGF-ß1 resulted in increased Hotair expression and triggered the EMT program. Interestingly, ablation of Hotair expression by siRNA prevented the EMT program stimulated by TGF-ß1, and also the colony-forming capacity of colon and breast cancer cells. Furthermore, we observed that the colon CSC subpopulation (CD133(+)/CD44(+)) presents much higher levels of Hotair when compared with the non-stem cell subpopulation. These results indicate that Hotair acts as a key regulator that controls the multiple signaling mechanisms involved in EMT. Altogether, our data suggest that the role of Hotair in tumorigenesis occurs through EMT triggering and stemness acquisition.