Abstract C043: Hyperinsulinemia promotes pancreatic cancer progression by altering tumor metabolism
Bibliographic record
Abstract
Abstract Metabolic diseases, such as type 2 diabetes (T2D), insulin resistance, and obesity, often accompany pancreatic ductal adenocarcinoma (PDAC), and they are associated with reduced survival. Hyperinsulinemia is a common hallmark symptom shared by those disorders and is independently associated with reduced survival of PDAC patients. While it has been established that endogenous hyperinsulinemia accelerates PDAC initiation by promoting the formation of KRAS-driven pre-cancerous lesions, its role in the progression of established tumors remains poorly understood. This represents a major knowledge gap in our understanding of whether insulin needs to be monitored and controlled during PDAC treatment, as it is not typically considered in current treatment paradigms. We hypothesized that hyperinsulinemia promotes the progression of PDAC tumors. Using patient-derived PDAC organoids (PDOs) and a mouse model of metabolic disorders, we found that insulin may promote PDOs’ growth by reprogramming tumor metabolism. A High-fat diet (HFD) treatment that induces hyperinsulinemia, but not hyperglycemia in mice accelerated the growth of PDO-derived orthotopic xenografts. Importantly, the fasting insulin level showed a significant positive correlation with the endpoint tumor volume, suggesting that endogenous insulin may positively contribute to PDOs’ growth in vivo. To assess the direct effect of insulin on the growth and molecular profile of PDOs, we treated an early passage PDO line with different concentrations of insulin and glucose at physiologically relevant levels. We observed a ∼1.2-fold increase in cell number after 7 days of culture in high insulin (10 nM) conditions with high (15 mM) or physiological (6 mM) levels of glucose, relative to the low insulin control. Phosphoproteomic analysis demonstrated significantly greater PI3K/AKT/mTOR, but not RAF/MEK/ERK, activity under high insulin with high or physiological levels of glucose compared to the control, directing the investigation toward the metabolic effects of insulin. Consistently, unbiased proteomics profiling revealed that metabolic proteins were significantly enriched in both high insulin conditions, and interestingly insulin enriched different sets of proteins in various metabolic pathways depending on glucose levels. Together, our preliminary results suggest that hyperinsulinemia may enhance the growth and progression of PDAC by altering tumor metabolism to support cell growth. Further experiments are needed to functionally link the insulin-mediated metabolic changes with increased PDO growth, as well as testing the direct effect of endogenous insulin on PDAC cells in vivo. Citation Format: Jeffrey Lin, James D Johnson, David Schaeffer, Vincent Richard, Christoph Borchers, Janel L Kopp. Hyperinsulinemia promotes pancreatic cancer progression by altering tumor metabolism [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C043.
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".