Abstract 3359: Elucidating the oncogenic mechanism of the TAZ-CAMTA1 and YAP-TFE3 fusion proteins
Bibliographic record
Abstract
Abstract Introduction: Sarcomas are cancers that originate from mesenchymal-derived tissues and represent 1% of adult cancers and 15% of pediatric cancers. No effective medical therapy exists for sarcomas, and the 5-year survival of metastatic sarcomas is 16%. Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma where 90% of tumors contain a WWTR1-CAMTA1 gene fusion, whereas the other 10% contain a YAP1-TFE3 gene fusion. TAZ (WWTR1) and YAP are oncogenic transcriptional coactivators and paralogues of one another that are negatively regulated by the Hippo signaling pathway. Constitutive activation of TAZ/YAP is observed in many types of cancer, including sarcomas, however genetic alterations within the pathway are rare. The precise mechanism by which TAZ-CAMTA1 and YAP-TFE3 transform cells is poorly understood. Methods: NIH-3T3 and human sarcoma cell lines were transduced with TAZ-CAMTA1 or YAP-TFE3. Western blot and immunofluorescence were used to evaluate expression and localization of the fusion proteins. In vitro assays were used to assess hallmarks of cancer. Protein-protein interactions were identified through BioID-tandem mass spectrometry. Xenograft experiments in NSG mice with cell lines expressing the fusion proteins were performed to study in vivo hallmarks of cancer. Results: The TAZ-CAMTA1 and YAP-TFE3 fusion proteins contain the N-terminus of TAZ and YAP fused in frame to the C-terminus of CAMTA1 and TFE3, rendering the N-terminus of TAZ and YAP unresponsive to negative regulation by the Hippo pathway. Immunofluorescence revealed that the fusion proteins are localized within the nucleus in both sparse and confluent states, compared to TAZ and YAP which are only localized to the nucleus under sparse conditions. TAZ-CAMTA1 and YAP-TFE3 also promote anchorage-independent growth and increased proliferation. Mass spectrometry revealed differential protein-protein interactions between TAZ-CAMTA1 and/or YAP-TFE3 and the Crumbs complex (MPDZ, PATJ, RASSF8, AMOT, AMOTL1), SWI/SNF complex (ARID1A, ARID1B, SMARCC2, SMARCE1), the Mediator complex (MED12), and chromatin remodeling complexes, as compared to full length TAZ and YAP. Xenografts of transduced NIH-3T3 and SW872 cells showed that the fusion proteins drive tumorigenesis and metastasis in NSG mice. Conclusions: The data indicate that the oncogenic properties of TAZ-CAMTA1 and YAP-TFE3 can be explained by their nuclear enrichment, dysregulation of the upstream Hippo pathway, and interaction with key transcriptional regulatory proteins. Future in vitro and in vivo studies will elucidate additional mechanisms by which these fusion proteins transform cells and promote sarcomagenesis, potentially resulting in new therapeutic targets. Citation Format: Nicole Merritt, Dushyandi Rajendran, Zhen-Yuan Lin, Xiaomeng Zhang, Katrina Mitchell, Colleen Fullenkamp, Anne-Claude Gingras, Kieran Harvey, Munir Tanas. Elucidating the oncogenic mechanism of the TAZ-CAMTA1 and YAP-TFE3 fusion proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3359.
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) | 0.000 | 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) | 0.003 | 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".