Notch1 Deficiency Induces Tumor Cell Accumulation Inside the Bronchiolar Lumen and Increases TAZ Expression in an Autochthonous Kras LSL-G12V Driven Lung Cancer Mouse Model.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:34257546", "kind": "science-record", "revision": 6, "content_hash": "sha256:979d09c6f73c60898d042e78337aa8323ff944c360ef1305283211a777a53840", "created_at": "2026-11-01T15:41:43Z", "updated_at": "2026-11-01T21:25:45Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Notch1 Deficiency Induces Tumor Cell Accumulation Inside the Bronchiolar Lumen and Increases TAZ Expression in an Autochthonous Kras LSL-G12V Driven Lung Cancer Mouse Model.", "doi": "10.3389/pore.2021.596522", "pmid": "34257546", "authors": ["Lydia Meder", "Alexandra Florin", "Luka Ozretić", "Marieke Nill", "Mirjam Koker", "Sonja Meemboor", "Freddy Radtke", "Linda Diehl", "Roland T Ullrich", "Margarete Odenthal", "Reinhard Büttner", "Lukas C Heukamp"], "journal": "Pathology oncology research : POR", "year": 2021, "abstract": "Purpose: Abrogation of Notch signaling, which is pivotal for lung development and pulmonary epithelial cell fate decisions was shown to be involved in the aggressiveness and the differentiation of lung carcinomas. Additionally, the transcription factors YAP and TAZ which are involved in the Hippo pathway, were recently shown to be tightly linked with Notch signaling and to regulate the cell fate in epidermal stem cells. Thus, we aim to elucidate the effects of conditional Notch1 deficiency on carcinogenesis and TAZ expression in lung cancer. Methods: We investigated the effect of conditional Cre-recombinase mediated Notch1 knock-out on lung cancer cells in vivo using an autochthonous mouse model of lung adenocarcinomas driven by Kras LSL-G12V and comprehensive immunohistochemical analysis. In addition, we analyzed clinical samples and human lung cancer cell lines for TAZ expression and supported our findings by publicly available data from The Cancer Genome Atlas (TCGA). Results: In mice, we found induction of papillary adenocarcinomas and protrusions of tumor cells from the bronchiolar lining upon Notch1 deficiency. Moreover, the mutated Kras driven lung tumors with deleted Notch1 showed increased TAZ expression and focal nuclear translocation which was frequently observed in human pulmonary adenocarcinomas and squamous cell carcinomas of the lung, but not in small cell lung carcinomas. In addition, we used data from TCGA to show that putative inactivating NOTCH1 mutations co-occur with KRAS mutations and genomic amplifications in lung adenocarcinomas. Conclusion: Our in vivo study provides evidence that Notch1 deficiency in mutated Kras driven lung carcinomas contributes to lung carcinogenesis in a subgroup of patients by increasing TAZ expression who might benefit from TAZ signaling blockade.", "claims": [{"id": "claim-method", "statement": "The two-sided Student’s t-test and the Pearson Correlation Coefficient were used to analyze data for significant differences and correlations.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34257546", "locator": "sections[9] \"Statistics\" paragraph 2", "quote": "The two-sided Student’s t-test and the Pearson Correlation Coefficient were used to analyze data for significant differences and correlations."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The datasets presented in this study can be found in online repositories. 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This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": [], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": [], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:obtain_source_data blocked on data:accession_absent"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:34257546", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3389/pore.2021.596522", "sha256": "sha256:dc4d0e9a0361773d2e79d5a6d4789326858ee3d29c58fce6bb0457a88f1f2064", "bytes": 44806, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3389/pore.2021.596522", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8262161", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "asset:table:pmid:34257546:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:59b3d87d4e3fe0169c63b50ed97d5d84ffb8d3618bd52a25301d48dbd211170d", "bytes": 786, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[12]/table-wrap[1]#T1", "version": null, "note": "Putative loss-of-function NOTCH1 aberrations co-occur with KRAS mutations and genomic amplifications in human lung ADCs. A publicly available TCGA dataset provided 230 cases of lung ADCs [22] including the five listed cases which harbor putative loss-of-function genomic alterations in NOTCH1. KRAS alterations are listed accordingly.", "structure": {"pmcid": "PMC8262161", "section_index": 12, "section_title": "Co-Occurrence of Putative Loss-of-Function Mutations in NOTCH1 with Genomic KRAS Aberrations in Lung ADCs", "row_count": 6, "column_count": 3}, "table": {"label": "TABLE 1", "caption": "Putative loss-of-function NOTCH1 aberrations co-occur with KRAS mutations and genomic amplifications in human lung ADCs. A publicly available TCGA dataset provided 230 cases of lung ADCs [22] including the five listed cases which harbor putative loss-of-function genomic alterations in NOTCH1. KRAS alterations are listed accordingly.", "rows": [["Case", "Putative loss-of-function NOTCH1 alteration", "Genomic KRAS alteration"], ["TCGA-44-2657", "E256Q", "Amplification"], ["TCGA-44-7672", "D259N", "Amplification + G12A"], ["TCGA-50-5931", "D297G", "Not altered"], ["TCGA-55-1592", "D1815Gfs*19", "Amplification"], ["TCGA-67-3774", "P820L", "Amplification + G12F"]], "row_count": 6, "column_count": 3, "numeric_cells": 12, "header_rows": 1, "locator": "section[12]/table-wrap[1]#T1"}}, {"id": "asset:table:pmid:34257546:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:73ecb412e42a95572109bcd9e21b0767bf111461fa8cbf0de354461cdae3e006", "bytes": 1421, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[13]/table-wrap[1]#T2", "version": null, "note": "Clinicopathological characteristics. Histology, age at diagnosis and gender are correlated to the TAZ expression in the nucleus. Biopsy samples have been combined on tissue micro arrays comprising SCC (n = 38), ADC (n = 37) and SCLC (n = 32). Statistical analysis was performed using Pearson Correlation. R-values and p-values are indicated.", "structure": {"pmcid": "PMC8262161", "section_index": 13, "section_title": "Deletion of Notch1 Triggered TAZ Expression in Mutated Kras LSL-G12V Driven Lung Cancer", "row_count": 25, "column_count": 8}, "table": {"label": "TABLE 2", "caption": "Clinicopathological characteristics. Histology, age at diagnosis and gender are correlated to the TAZ expression in the nucleus. Biopsy samples have been combined on tissue micro arrays comprising SCC (n = 38), ADC (n = 37) and SCLC (n = 32). Statistical analysis was performed using Pearson Correlation. 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