Abstract A007: Calcitonin gene-related peptide (CGRP) and receptor activity-modifying protein 1 (RAMP1) drive tumor cell growth in early-onset human gastric cancer
Bibliographic record
Abstract
Abstract Introduction Global rates of gastric cancer (GC) are rising among individuals under the age of 50, yet the underlying drivers of early-onset GC remain unknown. Tumour cells are highly adaptive and exploit various components of their microenvironment, including nerves, to support and accelerate growth. In this study, we investigated the expression and function of the sensory neuropeptide CGRP and its receptor component RAMP1, aiming to uncover novel mechanisms by which cancer cells leverage neuropeptide signaling to promote tumor growth and potentially uncover new avenues to exploit in the treatment of early onset GC. Methods: We analyzed patient samples using multiplex immunohistochemistry (mIHC) to assess CGRP and RAMP1 expression across different histological and anatomical subtypes of human GC. RAMP1 expression was correlated with patient demographics and tumor characteristics, including age, pathological features and molecular/genomic subtypes. In addition, RAMP1 expression and association with patient survival were evaluated using data from The Cancer Genome Atlas (TCGA). Finally, we examined the function of CGRP on tumor cells using in vitro stimulation assays followed by RNA sequencing and Crispr/Cas9 deletion of RAMP1, to further interrogate the mechanism of CGRP activity. Results: Analysis of RAMP1 expression in human gastric tumors using TCGA data, revealed that RAMP1 expression was significantly associated with poorer patient outcomes. We next stained patient tumours using mIHC for RAMP1 and its ligand CGRP. Interestingly, we observed an increase in RAMP1 expression in early onset GC patients. CGRP was abundantly expressed in stromal regions, potentially highlighting nerve fiber localization in close proximity to tumor cells. Notably, in subset of patients, over 50% of tumor cells were capable of producing CGRP. Finally, CGRP stimulation enhanced tumor cell growth in a RAMP1-dependent manner, inducing genes linked to proliferation, metabolism, and migration. Conclusion: Our findings uncover a potential role for CGRP-RAMP1 signaling in driving tumor growth in early-onset GC. This neuropeptide axis may represent a critical mechanism by which young patients' tumors exploit neural cues for progression. Further investigation into age-specific drivers of GC is warranted, and CGRP-RAMP1 signaling emerges as a promising therapeutic target in this context. Citation Format: Pavitha Parathan, Kelly Tran, Liam Neil, Annalisa L E. Carli, Yang Liao, Jessica D G. Duarte, Anne Huber, Bhupinder Pal, Isaac M. Chiu, Conor J. Kearney, Wei Shi, John M. Mariadason, David S. Williams, Michael Buchert, Lisa A. Mielke. Calcitonin gene-related peptide (CGRP) and receptor activity-modifying protein 1 (RAMP1) drive tumor cell growth in early-onset human gastric cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr A007.
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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".