Abstract LB059: Fructose transporter (SLC2A5)-dependent regulation of STAT3 expression in cancer cells metastasis
Bibliographic record
Abstract
Abstract Endoplasmic reticulum (ER) stress plays an integral part during cancer progression and is utilized as an adaptive mechanism in stressful environments. During tumour formation, cancer cells experience a hostile microenvironment composed of a lack of oxygen, nutrients and lipids and an acidic pH and they undergo high metabolic demands, with increased protein production and cellular growth. Using an ER Stress reporter assay we discovered that silencing the fructose transporter SLC2A5 (GLUT5) gene and, consequently, reduced uptake of fructose resulted in inhibition of the IRE1/spXBP1 arm of the ER stress response. Furthermore, we showed that the loss of the fructose transporter inhibits cancer cell migration and proliferation in MIA-PaCa-2 pancreatic cancer cells. RPPA analysis of SLC2A5-deficient pancreatic cancer cells identified STAT3 playing an essential role in the response to reduced fructose uptake. In the absence of SLC2A5, there was a significant decrease in the abundance of STAT3 mRNA and protein, as well as decreased STAT3 transcriptional activity. Transcriptional analysis revealed that the STAT3 gene is regulated by ER stress via the IRE1α/spXBP1 pathway and that it was responsible for reduced abundance of STAT3 in SLC2A5-deficient pancreatic cancer cells. STAT3 association with the mitochondria was also reduced in the absence of the fructose transporter. Membrane contact SPLICS analysis revealed the loss of the close mitochondrial-ER contacts in SLC2A5-deficient MIA-PaCa-2 cells. Furthermore, flow cytometry analysis of calcium fluxes indicated a disruption in the calcium transfer between the ER and the mitochondria. Reduced calcium transfer to mitochondria in SLC2A5-deficient MIA-PaCa-2 cells was accompanied by increased amount of reactive oxygen species (ROS). Taken together, these findings indicated that a deficiency in the fructose transporter SLC2A5 in MIA-PaCa-2 pancreatic cancer cells resulted in reduced STAT3 expression and activity, a reduction of mitochondria-ER contact sites, reduced calcium transfer to the mitochondria and increased ROS production in the mitochondria, all contributing to disrupted mitochondrial architecture and function. Citation Format: Jody Groenendyk, Myriam Pujol, Ning Dai, Izabela Quest, Ayshna Diya, Jingfeng Tang, Luis B. Agellon, Marek Michalak. Fructose transporter (SLC2A5)-dependent regulation of STAT3 expression in cancer cells metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB059.
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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) | 0.004 | 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".