Abstract A086: TFEB protects pancreatic cancer cells against nucleolar stress
Bibliographic record
Abstract
Abstract Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate among cancers. Despite its limited efficacy, gemcitabine is widely used in PDAC regimens. Chemoresistance to gemcitabine is likely a contributor to its poor effectiveness. Our previous research has shown that gemcitabine induces a cytoprotective autophagy and lysosomal response in pancreatic cancer cells. Further understanding of the mechanisms behind this autophagy and lysosomal response could lead to new therapeutic opportunities. It is known that gemcitabine can cause DNA replication arrest, double-strand breaks, and possibly nucleolar stress. Herein, we aim to specifically determine whether gemcitabine induces nucleolar stress and if this nucleolar stress triggers a cytoprotective response. Indicative of nucleolar stress, we demonstrate nucleoplasmic localization of nucleolin and nucleolar morphological changes upon gemcitabine treatment. Treatment of cells with the nucleolar stress inducer CX-5461 leads to an autophagy and lysosomal response as monitored by increased LC3 and LAMP1 puncta, and mature cathepsin B levels. Furthermore, enriched nuclear localization of the master regulator of autophagy and lysosomal function, TFEB, is observed in CX5461-treated cells (as detected by immunofluorescence and subcellular fractionation). This nuclear enrichment of TFEB correlates with the enrichment of faster migrating forms of TFEB (indicative of post-translational modification changes) as detected by immunoblotting. Through clonogenic assays, PDAC cells with reduced TFEB function (PDAC-shTFEB) demonstrate higher sensitivity than control cells to CX-5461. Furthermore, PDAC-shTFEB cells express higher levels of apoptotic markers upon CX-5461 treatment. Overall, our data provide the first evidence that nucleolar stress induces a TFEB-dependent protective response. Given that our work was performed in cells without functional wild-type p53 signaling, TFEB could act as a sensor of nucleolar stress relaying a protective response and assisting cells to engage in timely and coordinated action to cope with stress. Therefore, our results provide further support for the involvement of TFEB in the chemoresistance of PDAC cells. Citation Format: Florence Mc Duff, Laure Bessy, Benoit Marchand, Marie-Josee Boucher. TFEB protects pancreatic cancer cells against nucleolar stress [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A086.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".