Abstract A18: Ccn1 expression by fibroblasts is required for melanoma metastasis
Bibliographic record
Abstract
Abstract Metastatic melanoma is highly fatal. Within the tumor microenvironment, the role of cancer-associated fibroblasts (CAFs) in melanoma metastasis and progression is relatively understudied. Matricellular proteins of the CCN family are emerging targets for cancer therapy. Anti-CCN2 (CTGF) strategies are under clinical development; however, the role of CCN1 (cyr61) in cancers is unclear. Herein, we use bioinformatic analyses to report that the CCN1 is overexpressed, in a fashion independent of BRAF mutational status, in melanoma. In human melanoma patients, CCN1 expression negatively correlates with overall survival, disease-free, and metastasis-free survival (p<0.03). CCN1 expression positively correlates with expression of stroma and neovascularization markers. To assess the role of CAFs in melanoma progression, we used C57BL/6 mice expressing a tamoxifen-dependent cre recombinase expressed under the control of a fibroblast-specific promoter/enhancer (COL1A2) to delete CCN1 postnatally in fibroblasts. Mice deleted or not for CCN1 in fibroblasts were injected subcutaneously with B16-F10 melanoma cells. Loss of CCN1 in CAFs did not result in reduced CAF activation, as detected by staining with anti-α-smooth muscle actin antibodies, but resulted in reduced extracellular matrix surrounding tumors, as detected by trichrome stain, and reduced tumor-induced neovascularization, as detected by staining with anti-CD31 antibodies. CCN1-deficient skin showed reduced expression of mRNAs encoding collagen crosslinking enzymes (PLOD2 and LOX) and impaired formation of collagen fibers, as determined by electron microscopy. Tumor growth was not affected by loss of CCN1 from tumor stroma; however, micrometastasis to the lung was severely impaired (p<0.001). Our results provide new insights into the crosstalk among different cell types in the tumor microenvironment and confirm the essential role of CAFs in metastasis and tumor neovascularization. Our data are consistent with the hypothesis that CAFs are essential for melanoma metastasis and that CCN1 is a therapeutic target for melanoma. Citation Format: James Hutchenreuther, Katherine Quensel, Krista Vincent, Lynne-Marie Posrovit, Andrew Leask. Ccn1 expression by fibroblasts is required for melanoma metastasis [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A18.
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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 | 0.001 | 0.001 |
| 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".