Loss of ULK1 impairs autophagy activation, spheroid viability, and tumor progression in epithelial ovarian cancer
Bibliographic record
Abstract
Abstract Introduction: Epithelial ovarian cancer (EOC) remains a leading cause of gynecological cancer-related deaths due its late diagnosis and the absence of effective treatments for chemo-resistant disease. EOC metastasizes through peritoneal dissemination, often forming multicellular spheroids, in which autophagy—a cell survival mechanism—is induced, requiring ULK1 (Unc-51-like kinase 1) activity. Our study aims to further understand the role of ULK1 in EOC tumor growth and metastasis. Methods: Using CRISPR/Cas9 technology, we ablated the ULK1 gene in EOC cell lines OVCAR8 and HEYA8, and the fallopian tube derived FT190 control line. Western blotting confirmed ULK1 loss and key autophagy markers. Autophagic flux was assessed using fluorescence microscopy and cell viability by Trypan Blue, Cell Titer-Glo, and Caspase-Glo assays. We tested sensitivity to carboplatin and paclitaxel treatments in cell culture, while bioluminescent imaging monitored tumor progression of xenograftsULK1KO. Immunohistochemistry (IHC) was performed to assess Ki67 for cell proliferation and cleaved caspase-3 for apoptosis. Results: Our results show that ULK1 loss leads to impaired autophagy in EOC spheroids, with reduced LC3 processing and elevated p62 levels. Intriguingly, FT190 cells maintained autophagy which correlated with elevated ULK2 expression. All cell lines lacking ULK1KO had reduced spheroid cell viability and spheroid integrity. Surprisingly, ULK1 loss led to differential sensitivity to chemotherapy agents carboplatin and paclitaxel between OVCAR8 and HEYA8 cells. ULK1 deficiency reduced tumor burden in xenografted mice, although differences were observed in tumor growth rate and extent of metastasis between OVCAR8 and HEYA8 cells. Furthermore, Ki67 and cleaved caspase-3 staining revealed reduced cell proliferation and increased apoptosis respectively in tumors derived from ULK1KO cells. Conclusions: ULK1 is required for EOC spheroid formation and cell survival while in suspension likely through its regulation of autophagy, but it may have a lesser role for autophagy regulation in precursor cells. ULK1 deficiency does not increase EOC cell sensitivity to standard-of-care chemotherapy, possibly indicating that other therapeutic strategies would be needed to synergize with autophagy inhibition for EOC treatment.. Altogether, ULK1 may have a multifaceted role in EOC beyond autophagy regulation, by contributing to early dissemination of as spheroids and establishment of secondary tumors
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".