Abstract PR09: Pancreatic cancer cachexia is mediated by tumor-derived PTHrP
Bibliographic record
Abstract
Abstract Purpose: Our prior work has established that metastasis is initiated by PTHrP-driven mechanisms in PDAC. PTHLH (the gene encoding the PTHrP protein) is directly adjacent to and co-amplified along with KRAS, and this amplicon is a marker of squamous/quasi-mesenchymal/basal-like PDAC subtypes. Thus, PTHrP marks highly aggressive subsets of PDAC patients. We have generated KPCY-PthlhLoxP (herein KPCY-PthrpcKO) mice and observed a near doubling of overall survival relative to KPCY controls. Intriguingly, recent evidence has emerged for PTHrP’s role in cachexia-associated adipose tissue wasting and we posit that the dramatic survival extension in KPCY-PthrpcKO mice may be due to reduced cachexia. Results: In PDAC patients, PTHrP is co-amplified along with KRAS and correlates with significantly decreased overall survival. We generated KPCY-PthrpcKO mice and showed that they have reduced tumor burden and dramatically increased overall survival relative to KPCY controls. In parallel experiments, we treated mice with an anti-PTHrP neutralizing monoclonal antibody, which similarly reduced tumor growth and extended survival. Upon further analysis, we observed that the overall body condition of KPCY-PthrpcKO mice (and anti-PTHrP treated KPCY mice) was greatly improved, with less loss of adipose and muscle tissue. Mechanistic studies revealed that tumor cell-derived PTHrP signaling to adipocytes in white adipose tissue depots mediates cachexia. Specifically, we found that adipose tissue wasting and lipolysis were greatly reduced upon deletion or pharmacological inhibition of PTHrP. In the same vein, we uncovered that PTHrP is driving an adipocyte “browning” process, a phenomenon where energy-storing white adipocytes transdifferentiate into an energy-expending brown adipocyte-like state (often referred to as “beige” adipocytes). Preliminary results indicate direct tumor cell-adipocyte crosstalk with tumor cell secreted PTHrP binding to its cognate receptor, PTH1R, on adipocytes and activating a thermogenic (heat generating) gene program, likely through a PTH1R-PKA-CREB1 signaling axis. We additionally found that muscle wasting was reduced in KPCY-PthrpcKO mice and anti-PTHrP neutralizing antibody treated KPCY mice. Thus, genetic deletion and pharmacological inhibition of PTHrP in vivo led to a profound reduction in cachexia-related adipose tissue wasting and muscle atrophy. Re-introduction of PTHrP into a PDAC cell line with low cachexia-inducing potential (and low baseline PTHrP) dramatically increased the degree of cachexia observed upon orthotopic implantation. Additionally, mice implanted with PTHrP overexpressing tumor cells had a reduction in overall survival along with decreased overall body condition. Therefore, PTHrP is both necessary and sufficient to induce cachexia. Conclusions: This work has demonstrated the importance of the previously unappreciated roles of PTHrP signaling in driving pancreatic cancer cachexia and adipose tissue browning, and future studies will look to translate anti-PTHrP therapy into clinical trials. Citation Format: Yamini Ogoti, Jessica Peura, Calvin Johnson, Ekaterina Korobkina, Maximilian Wengyn, Robert J. Norgard, Richard Kremer, David A. Guertin, Jason R. Pitarresi. Pancreatic cancer cachexia is mediated by tumor-derived PTHrP [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 PR09.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".