Molecular Evaluation of Patient-Derived Colorectal Cancer Explants as a Pre-clinical Mouse Model of Colorectal Cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE35144 | GEO | 2012/06/07
SECONDARY ACCESSION(S): PRJNA150711
REPOSITORIES: GEO
Similar Datasets
Project description:Mouse models have been developed to investigate colorectal cancer etiology and evaluate new anti-cancer therapies. While genetically engineered and carcinogen-induced mouse models have provided important information with regard to the mechanisms underlying the oncogenic process, xenograft models remain the standard for the evaluation of new chemotherapy and targeted drug treatments for clinical use. However, it remains unclear if drug efficacy data obtained from xenograft models translate into clinically-relevant treatment modalities. In this study, we have generated a panel of 28 patient-derived colorectal cancer explants (PDCCEs), an extension of our previous work, by direct transplantation of human colorectal cancer (CRC) tissues into NOD-SCID mice. A comprehensive histological and molecular evaluation of PDCCEs and their corresponding patient tumor demonstrates that PDCCEs maintain histological features and global biology through multiple passages. Furthermore, we demonstrate that in vivo sensitivity of PDCCEs to oxaliplatin can predict patient outcomes. Our findings suggest that PDCCEs maintain similarity to the patient tumor from which they are derived and can serve as a reliable preclinical model that can be incorporated into future strategies to optimize individual therapy for patients with CRC. 28 human primary colorectal and 37 mouse derived colorectal explant tumors
2012-06-06 | E-GEOD-35144 | biostudies-arrayexpress
Project description:Phenotypic plasticity is a major driver of cancer progression, metastasis, and treatment resistance. However, the principles governing human cancer plasticity associated with poor prognosis remain poorly understood due to the lack of in vitro models. Here we identified a unique cancer cell state at single-cell resolution to predict poor prognosis across several human cancers with different clinical features, especially colorectal cancer (CRC) progression and metastasis, named the poor prognostic plastic state (PPPS). A functional patient-derived organoid xenograft (PDOX) model was developed to capture and maintain the PPPS in CRC. With a marker gene of MSLN (encoding mesothelin), this model was used to validate the role of the PPPS in promoting CRC metastasis. Moreover, precise manipulation of human cancer plasticity through the PPPS allows us to identify small-molecule inhibitors of non-canonical IKKs to promote malignancy, with clinical implications for targeting the PPPS to prevent CRC progression and metastasis.
2024-04-17 | GSE261004 | GEO
Project description:Phenotypic plasticity is a major driver of cancer progression, metastasis, and treatment resistance. However, the principles governing human cancer plasticity associated with poor prognosis remain poorly understood due to the lack of in vitro models. Here we identified a unique cancer cell state at single-cell resolution to predict poor prognosis across several human cancers with different clinical features, especially colorectal cancer (CRC) progression and metastasis, named the poor prognostic plastic state (PPPS). A functional patient-derived organoid xenograft (PDOX) model was developed to capture and maintain the PPPS in CRC. With a marker gene of MSLN (encoding mesothelin), this model was used to validate the role of the PPPS in promoting CRC metastasis. Moreover, precise manipulation of human cancer plasticity through the PPPS allows us to identify small-molecule inhibitors of non-canonical IKKs to promote malignancy, with clinical implications for targeting the PPPS to prevent CRC progression and metastasis.
2024-04-17 | GSE261012 | GEO
Project description:Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and might be more relevant preclinical models to evaluate effective therapeutic agents. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer models. From 86 unsupervised surgical colon sample collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinosis and 14 metastases. Our histological and molecular characterization of patient tumors, first passage on mice and later passages includes the sequence of key genes involved in CRC (ie APC, KRAS, TP53), CGH array and transcriptomic analysis. This comprehensive characterization demonstrates that our collection recapitulates the clinical situation regarding the histopathological and molecular diversity of colorectal cancers. Moreover, patient tumors and corresponding models are clustering together which gives the opportunity to look for relevant signatures and comparison studies between clinical and preclinical data. Hence, we performed pharmacological monotherapy studies with standard of care for colon cancer (5-FU, oxaliplatin, irinotecan, cetuximab). Through this extensive in vivo analysis, we have compared the molecular profile with the drug sensitivity of each tumor models, and run an equivalent of a cetuximab phase II clinical trial in a preclinical setting. Our results confirm the key role of KRAS mutation in the cetuximab resistance and demonstrate that such collection could bring benefit to evaluate novel targeted therapeutic strategies and potentially help the stratification strategy for cancer patients according to molecular marker. This set correspond to 82 CGH profiles, with 7 samples from patient tumor and 75 samples from mouse xenograft at different passages P0 to P9. All hybridizations are performed with Human CGH 244K Agilent arrays (amadid 014693) in dual color with Human DNA Promega (sex matched) as reference. ID for biosources without an -Px suffix correspond to tumor patients. ID with a suffix correspond to xenograft with 0 for the first passage.
2012-07-27 | E-MTAB-991 | biostudies-arrayexpress
Project description:Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and might be more relevant preclinical models to evaluate effective therapeutic agents. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer models. From 86 unsupervised surgical colon sample collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinosis and 14 metastases. Our histological and molecular characterization of patient tumors, first passage on mice and later passages includes the sequence of key genes involved in CRC (ie APC, KRAS, TP53), CGH array and transcriptomic analysis. This comprehensive characterization demonstrates that our collection recapitulates the clinical situation regarding the histopathological and molecular diversity of colorectal cancers. Moreover, patient tumors and corresponding models are clustering together which gives the opportunity to look for relevant signatures and comparison studies between clinical and preclinical data. Hence, we performed pharmacological monotherapy studies with standard of care for colon cancer (5-FU, oxaliplatin, irinotecan, cetuximab). Through this extensive in vivo analysis, we have compared the molecular profile with the drug sensitivity of each tumor models, and run an equivalent of a cetuximab phase II clinical trial in a preclinical setting. Our results confirm the key role of KRAS mutation in the cetuximab resistance and demonstrate that such collection could bring benefit to evaluate novel targeted therapeutic strategies and potentially help the stratification strategy for cancer patients according to molecular marker. This set correspond to 82 CGH profiles, with 7 samples from patient tumor and 75 samples from mouse xenograft at different passages P0 to P9. All hybridizations are performed with Human CGH 244K Agilent arrays (amadid 014693) in dual color with Human DNA Promega (sex matched) as reference. ID for biosources without an -Px suffix correspond to tumor patients. ID with a suffix correspond to xenograft with 0 for the first passage.
2012-07-27 | E-MTAB-992 | biostudies-arrayexpress
Project description:Claret2009 - Predicting phase III overall survival in colorectal cancer
This model is described in the article:
Model-based prediction of
phase III overall survival in colorectal cancer on the basis of
phase II tumor dynamics.
Claret L, Girard P, Hoff PM, Van
Cutsem E, Zuideveld KP, Jorga K, Fagerberg J, Bruno R.
J. Clin. Oncol. 2009 Sep; 27(25):
4103-4108
Abstract:
PURPOSE: We developed a drug-disease simulation model to
predict antitumor response and overall survival in phase III
studies from longitudinal tumor size data in phase II trials.
METHODS: We developed a longitudinal exposure-response
tumor-growth inhibition (TGI) model of drug effect (and
resistance) using phase II data of capecitabine (n = 34) and
historical phase III data of fluorouracil (FU; n = 252) in
colorectal cancer (CRC); and we developed a parametric survival
model that related change in tumor size and patient
characteristics to survival time using historical phase III
data (n = 245). The models were validated in simulation of
antitumor response and survival in an independent phase III
study (n = 1,000 replicates) of capecitabine versus FU in CRC.
RESULTS: The TGI model provided a good fit of longitudinal
tumor size data. A lognormal distribution best described the
survival time, and baseline tumor size and change in tumor size
from baseline at week 7 were predictors (P < .00001).
Predicted change of tumor size and survival time distributions
in the phase III study for both capecitabine and FU were
consistent with observed values, for example, 431 days (90%
prediction interval, 362 to 514 days) versus 401 days observed
for survival in the capecitabine arm. A modest survival
improvement of 39 days (90% prediction interval, -21 to 110
days) versus 35 days observed was predicted for capecitabine.
CONCLUSION: The modeling framework successfully predicted
survival in a phase III trial on the basis of capecitabine
phase II data in CRC. It is a useful tool to support
end-of-phase II decisions and design of phase III studies.
This model is hosted on
BioModels Database
and identified by:
MODEL1708310001.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-08-31 | MODEL1708310001 | BioModels
Project description:Despite the connection to distinct mucus-containing colorectal cancer (CRC) histological subtypes, the role of secretory cells, including goblet and enteroendocrine (EEC) cells, in CRC progression has been underexplored. Analysis of TCGA and single cell RNA sequencing data demonstrates that multiple secretory progenitor populations are enriched in BRAF-mutant CRC patient tumors and cell lines. Enrichment of EEC progenitors in BRAF-mutant CRC is maintained by DNA methylation and silencing of NEUROD1, a key gene required for differentiation of EECs. Mechanistically, secretory cells and the factors they secrete, such as Trefoil factor 3, are shown to promote colony formation and activation of cell survival pathways in the entire cell population. We further identify LSD1 as a critical regulator of secretory cell specification in vitro and in a colon orthotopic xenograft model, where LSD1 loss reduces tumor growth and metastasis. This work establishes EEC progenitors, in addition to goblet cells, as targetable populations in BRAF-mutant CRC and identifies LSD1 as a therapeutic target in secretory lineage-containing CRC.
2021-06-21 | GSE167262 | GEO
Project description:Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide. Different pathological pathways and molecular drivers have been described and some of the associated markers are used to select effective anti-neoplastic therapy. This dataset is part of ColPortal, a platform that integrates transcriptomic, microtranscriptomic, methylomic and microbiota data of patients with colorectal cancer. ColPortal also includes information of histological features and digital histological slides from the study cases.
2019-08-23 | GSE136194 | GEO
Project description:Dysfunction of cell cycle genes can lead to mitosis disruption and chromosomal instability (CIN), which is blamed for poor prognosis in colorectal cancer (CRC) patients, no matter with chemotherapy or not. Discovery therapeutic targets to abnormal cell cycle pathways in CRC may help to improve current therapy. By genome-widely profiling of differential expressed genes in 54 pairs of human colorectal tumor with matched normal mucosa, we found a functional enrichment in PLK1 signaling. Tumors with enriched PLK1 signaling are accompanied with dysfunction pathways related to cell cycle. Total PLK1 and phosphorylated PLK1 protein expression are associated with tumor recurrence and poor overall survival in a cohort of CRC patients. Combining PLK1 inhibitor with oxaliplatin shows a synergize effect to suppress the growth of CRC cell lines, xenograft tumors, preclinical patient-derived organoid and patient-derived xenograft tumors. RNA-seq data reveals that the cell cycle pathways were activated in oxaliplatin group but inhibited after PLK1 inhibitor treatment. CDC7 may be a key downstream effector of PLK1 induced oxaliplatin resistance and can be druggable. Further investigation showed that PLK1 inhibitor suppress the CDC7 expression via c-MYC transcriptional control. A strong positive correlation between PLK1 and CDC7 has been further confirmed in patients. Strikingly, functional studies confirm that combining CDC7 inhibitor with oxaliplatin can recapitulate the synergize effect in various CRC models, highlighting pharmacological target PLK1-MYC-CDC7 signaling as a potential therapeutic strategy for oxaliplatin based chemotherapy.
2023-10-24 | GSE160089 | GEO
Project description:Intra-tumor heterogeneity of tumor-initiating cell (TIC) activity drives colorectal cancer (CRC) progression and therapy resistance. Here, we used single-cell mRNA-sequencing (scRNA-seq) of patient-derived CRC models to decipher distinct cell subpopulations based on their transcriptional profiles. Cell type-specific expression modules of stem-like, transit amplifying-like, and differentiated CRC cells resemble differentiation states of normal intestinal epithelial cells. Strikingly, identified subpopulations differ in proliferative activity and metabolic state. In summary, we here show at single-cell resolution that transcriptional heterogeneity identifies functional states during TIC differentiation. Targeting transcriptional states associated to cancer cell differentiation might unravel vulnerabilities in human CRC.
2021-05-07 | PXD018230 | Pride