A249 ROLE OF LRP6 IN KRAS AND BRAF MUTATED COLORECTAL CANCER
Bibliographic record
Abstract
Colorectal cancer (CRC) represents the second leading cause of death worldwide. Self-renewal of the intestinal epithelium is tightly regulated by intracellular signaling pathways which control stem cell proliferation and differentiation. It has been previously reported that effectors of the Wnt/β-catenin and KRAS/BRAF/MEK/ERK pathways are often mutated in early stages of CRC, leading to sustained activation of these pathways. Whereas KRAS/ MAPK and canonical Wnt/β-catenin pathways are critical for intestinal tumorigenesis, mechanisms integrating these two important signaling pathways during CRC development are however unknown. We recently demonstrated that transformation of normal intestinal epithelial cells (IEC) by oncogenic forms of KRAS or BRAF was associated with a marked increase in phosphorylation of the Wnt co-receptor LRP6 and in β-catenin/TCF4 transcriptional activity. Notably, LRP6 phosphorylation was significantly increased in human colorectal tumors, including adenomas, in comparison with healthy adjacent normal tissues (Lemieux et al., 2015). These results suggest that LRP6 activation might represent a unique point of convergence between KRAS/MAPK and Wnt/β-catenin signaling during colorectal oncogenesis. The aim of this study was to determine the role of LRP6 in the anchorage-independent growth of KRAS and BRAF mutated human CRC cells. To analyze the role of LRP6 in human CRC cells, we used siRNA to specifically knockdown LRP6 expression. The cell lines analyzed displayed characteristic mutations: HCT116 (mutated for β-catenin and KRAS), HT29 (mutated for APC and BRAF) and SW480 (mutated for APC and KRAS). LRP6 phosphorylation and expression was analyzed by qPCR and Western blot. The effect of MEK inhibition on LRP6 phosphorylation was also evaluated by treating cells with CI1040 (2µM). Anchorage-independent growth was evaluated by culturing cells in soft agar for 10–15 days. Strong expression of LRP6 protein was observed in all CRC cell lines analyzed. Treatment of cells with the MEK inhibitor CI1040 (4h and 24h) significantly reduced LRP6 phosphorylation on serine 1490 and threonine 1572 suggesting a link between MEK/ERK signaling pathway and LRP6 activation. Most interestingly, LRP6 silencing dramatically inhibited the capacity of HCT116, HT29 and SW480 cells to grow under anchorage-independent conditions. Altogether these results suggest that LRP6 activation controls growth of CRC cells exhibiting KRAS or BRAF mutation, suggesting that this coreceptor might represent a novel therapeutic target for CRC associated with these mutations. CHUS
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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 | 0.000 |
| 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".