Abstract 2436: CIRBP is a functional mediator of leptomeningeal metastasis
Bibliographic record
Abstract
Abstract Background: Cold-Inducible RNA Binding Protein (CIRBP) has been implicated in cancer initiation. Moreover, we have previously identified an association of CIRBP with the invasive growth of parenchymal brain metastases. Using a patient-derived xenograft (PDX) model, in which cells implanted in the mouse mammary fat pad spontaneously metastasize to the leptomeninges, we identified CIRBP as being elevated in leptomeningeal metastases (LM) compared to matched primary mammary tumors. LM grow in the subarachnoid space that harbors the cerebral spinal fluid (CSF). The leptomeninges represent an inhospitable environment for disseminated cancer cells since the CSF is mitogen and nutrient poor. To investigate the importance of CIRBP for metastatic breast cancer cells in the leptomeninges, we stably reduced CIRBP expression in MDA-MB-231 cells and performed mammary fat pad and cranial injections. CIRBP knockdown had no influence on primary tumor growth, but diminished growth within the brain. Hypothesis: We hypothesize that CIRBP functions as a stress response protein enabling cancer cells to grow in the harsh environment of the CSF. Results: In response to various cellular stressors, such as hypothermia, hypoxia or UV irradiation, CIRBP can translocate from the nucleus to the cytoplasm. We show that culturing MDA-MB-231 cells in artificial CSF (aCSF) also causes CIRBP relocation from nucleus to cytoplasm. Using RNA-IP approaches, we have identified mRNAs bound by CIRBP in breast cancer cells treated with aCSF. Ultimately, we will determine whether any of the identified CIRBP-regulated targets contribute to the formation of LM. Finally, we have generated CIRBP variants that are confined either to the nucleus or the cytoplasm. We are currently assessing the ability of these compartment-restricted CIRBP proteins to promote the formation of central nervous system metastases. Conclusions: We have identified CIRBP as a promoter of leptomeningeal metastasis. Our results have begun to reveal the mechanisms through which CIRBP mediates this process. Citation Format: Rima Ezzeddine, Matthew Dankner, Paul Savage, Steven Hebert, William Brothers, Matthew G. Annis, Sarah M. Maritan, Marc R. Fabian, Claudia Kleinman, Morag Park, Peter M. Siegel. CIRBP is a functional mediator of leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2436.
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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) | 0.001 | 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) | 0.008 | 0.002 |
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".