Functional requirement for RGD and PKD domains of GPNMB in breast cancer metastasis
Bibliographic record
Abstract
3681 The morbidity and mortality associated with breast cancer results primarily from the spread of cancer cells from the breast to secondary organs. Currently, there are very few available therapies that effectively target breast cancer metastases. Identification and characterization of the functional mediators of metastasis is critical to the development of targeted anti-metastatic therapies. We have recently identified GPNMB (Osteoactivin, DC-HIL, HGFIN) as a novel mediator of breast cancer metastasis to bone. Here, we show the GPNMB protein is detectable in a subset of human breast cancer cell lines, but undetectable in normal breast epithelial cells. Furthermore, GPNMB is highly expressed in in vivo selected, aggressively lung-metastatic breast cancer cells, and ectopic expression of this gene in 66cl4 mammary carcinoma cells is sufficient to promote primary tumor growth and spontaneous lung metastases in vivo. These results argue that GPNMB may function as a more general regulator of breast cancer metastasis. To further investigate the relevance of GPNMB expression in human breast cancer, we have analyzed the gene expression profiles from 3 independent datasets comprising 99, 118, and 295 human breast tumors. Kaplan-Meier analysis reveals significant correlations in each dataset, between increased GPNMB expression and shorter metastasis-free and overall survival times. An increasing body of literature is emerging, linking high levels of GPNMB expression with progression of diverse cancer types. Indeed, a GPNMB-targeted, cytotoxin conjugated antibody (CR011 vc-MMAE) is currently being investigated in Phase I clinical trials as a therapy for patients with Stage III/IV melanoma. Despite these observations, very little known about the metastasis-promoting functions of this protein. To further our understanding of GPNMB-dependent pro-metastatic effects, we have generated mutations that disrupt specific domains within the protein. GPNMB is a type I transmembrane glycoprotein with an extracellular integrin recognition motif (RGD), a putative ligand binding domain (PKD), a single transmembrane domain and a short cytoplasmic tail. Our data show that GPNMB enhances the invasive capacity of breast cancer cells in a PKD-dependent manner and promotes adhesion to endothelium in an RGD dependent manner. Due to its role in promoting endothelial adhesion and invasion, we are currently developing a model to monitor GPNMB-dependent extravasation of breast cancer cells in vivo. Together, these results offer mechanistic insight into the metastogenic roles of GPNMB, a molecule that is highly expressed in aggressive human breast cancers. Moreover, this data provides further rationale toward the pursuit of GPNMB-targeted therapies for breast cancer.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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 teacher head, 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".