Abstract LB-282: Cancer-specific motogenic signals induce collective migratory pattern in myofibroblasts via increased tight junction formation
Bibliographic record
Abstract
Abstract Tumor cells recruit normal fibroblasts through paracrine signals, and transform them into cancer-associated fibroblasts (CAFs) at the cancer invasion front, a lesion known as desmoplasia. CAFs have increased proliferation, migration and contractile behaviour, all regulated by a specific biological program, the fibroblast-to-myofibroblast transdifferentiation. Since cancer cell-secreted factors are responsible for this effect, we hypothesized that the genetic background of individual tumor cells could cause diverse migratory potential in CAFs. To test this, we performed wound healing assays in 18Co normal colonic fibroblast monolayers and observed migratory patterns, upon stimulation with conditioned media (CM) from various colon cancer cell lines (i.e. HT29, SW480, SW620) with diverse genetic background. Statistical assessment of mean wound length, invasive growth potential and number of migrating cells, revealed that HT29 CM induced collective migration, while SW480/SW620 CM preferentially induced individual cell migration (p<0.01). Polarity assays showed that HT29-treated fibroblasts had increased direction-sensing compared to other CM (p<0.01). Moreover, alpha-smooth muscle actin immunocytochemistry and matrix metalloproteinase-2 ELISA revealed that all cancer CM induced the myofibroblastic phenotype in 18Co cells. This indicated that the polarized, collective migratory pattern in HT29-treated 18Co cells occurs probably due to specific motogenic effectors, regulated by the HT29 secretome. An in-house developed, powerful SILAC approach, allowed the relative quantification of HT29-treated and autocrine (18Co)-treated myofibroblast proteomes, aiming to elucidate key proteins, potentially regulating collective migration. Using stringent criteria, we identified 22 proteins with >2-fold increase in HT29-treated cells. Three of these (PLAU, TIMP1, ITGA2) might explain the acquisition of myofibroblastic phenotype, since they are previously-known markers. Notably, Claudin-11 (CLDN11), a tight-junction protein, was found to be increased (2.5-fold) in HT29-treated 18Co cells. CLDN11 mRNA (PCR) and protein (Western Blot) levels were significantly increased in HT29-treated compared with SW480- and SW620-treated cells. siRNA-mediated knockdown of CLDN11 in 18Co cells suppressed the collective nature of migration. Conclusively, the paradoxical formation of tight junctions (TJs) during myofibroblast migration could be of considerable importance, since these apparatuses mainly characterize the epithelial phenotype, by providing epithelial shape and polarity. Our data suggest that upon overexpression in mesenchymal cells, TJs might allow collective, polarized and coordinated migration. Factors present in HT29 CM, responsible for CLDN11 upregulation in 18Co cells, are currently pursued via quantitative proteomics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-282. doi:10.1158/1538-7445.AM2011-LB-282
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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) | 0.004 | 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".