Single-cell analysis identified conserved epithelial programs associated with survival and resistance. Patient-derived organoid experiments then shifted platinum responses through SERCA2 activation or CCDC6 inhibition.
A team led from Helsinki analyzed single-cell transcriptomes from 50 treatment-naive ovarian high-grade serous carcinomas and 14 normal fallopian-tube epithelial samples. They identified transcriptional modules gained, lost or retained during carcinogenesis.
Two opposing conserved modules were associated with survival and genetic biases. An earlier developmental oxidative-phosphorylation program was associated with better survival. A later MAPK/NF-κB program marked a stable resistant state and loss of the major histocompatibility complex (MHC) class II antigen-presentation program present in its normal epithelial counterpart.
The modules were used to predict perturbations that could shift cell state. In patient-derived organoids, restraining endoplasmic-reticulum stress through SERCA2 activation drove an NF-κB-active, resistant phenotype. Inhibition of the DNA-repair regulator CCDC6 promoted the opposite, platinum-sensitive state.
Stress reduction accompanied greater resistance in this model. The experiments connect state predictions with functional treatment responses in human tumor models. They support further investigation of tissue-of-origin programs and platinum-response heterogeneity, while the survival associations and organoid perturbations do not establish benefit from module-guided treatment in patients.
A study connects aloperine binding and VPS34 lactylation to disrupted endosomal trafficking in lung cancer cells. Patient-derived organoids provided additional evidence of a stronger response to aloperine plus cisplatin than to either agent alone.
Assembloids from six patients reproduced their corresponding immunotherapy-response patterns. Component exchange and perturbations connected tumor WNT2B, fibroblast activin A and stem-like CD8 T cells, with low stromal LRP6 linked to resistance.
