Abstract A094: LIN28B/HMGA2 axis accelerates PDA by promoting oncogenic protein synthesis
Bibliographic record
Abstract
Abstract Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies and is projected to be the second leading cause of cancer deaths in the United States by 2030. Molecular characterization studies have described two major transcriptional subsets, called 'classical’ and ‘basal’. Basal PDAs (~25% of PDAs) have the worst overall survival and are the only class to act as an independent poor prognostic factor. The imminent entry of KRAS inhibitors into the clinic to treat PDA is poised to change this, but genetic experiments have predicted that the basal subtype of pancreatic cancer will be intrinsically resistant to these inhibitors. Therefore, there is an urgent need to understand basal PDA development and identify its unique vulnerabilities. We have discovered that the expression of the oncofetal RNA-binding protein LIN28B and its downstream target, the chromatin protein and high-mobility group (HMG) AT-hook 2 (HMGA2), are highly expressed in the basal subtype of PDA. We find LIN28B dramatically accelerates KRAS-driven PDA and acts as a potent oncogene in genetically engineered mouse models (GEMMs) of PDA. We find that HMGA2, downstream of LIN28B, controls cell growth and orchestrates the pathogenesis of basal PDA by hijacking a precise node of mRNA translation machinery. This raises the intriguing possibility that the aberrant activation of HMGA2 increases mRNA translation and may be one mechanism by which PDA attains the highly aggressive basal phenotype. Mechanistically, we observed that loss of HMGA2 results in decreased phosphorylation of S6K and EIF4B. Interestingly, this was independent of changes in MTOR activity. Loss of function studies using siRNA or inhibitors against PP2A restored pS6K and pEIF4B levels, and mRNA translation when HMGA2 was lost. It is known that reduction in pEIF4B levels leads to a reduction in mRNA translation of difficult-to-transcribe transcripts, such as the MYC oncogene. Indeed, loss of HMGA2 leads to a dramatic reduction in MYC protein levels but no changes to transcription or protein stability. Thus, our work has unveiled a new axis in LIN28B/HMGA2 high basal PDA that controls mRNA translation independent of MTOR, is reliant on PP2A, and controls cell growth through MYC translation. This work has the potential to identify innovative therapeutic strategies to combat this deadly subtype of PDA. Citation Format: Stephanie Dobersch, Sarah Cavendar, Naomi Yamamoto, Liberales Debraj Boila, Cindy Wladyka, Martine Roudier, Faiyaz Notta, Robert Eisenman, Andrew Hsieh, Sita Kugel. LIN28B/HMGA2 axis accelerates PDA by promoting oncogenic protein synthesis [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 A094.
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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) | 0.005 | 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".