Dataset Information

Increased cholesterol biosynthesis identified as a key feature and a therapeutic target of cancer stem cells as revealed by proteomic comparison of clinical breast cancer tissue and corresponding patient-derived xenografts and mammospheres

ABSTRACT: Cancer stem cells (CSCs) comprise a small subpopulation of undifferentiated cancer cells with the ability to self-renew and give rise to the heterogeneous cancer cell lineages that form tumorous masses. Thus, tumor eradication may be greatly improved by specifically targeting CSCs, as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed patient-derived xenograft (PDX) tumors from ER-negative breast cancer patient tissue from which we isolated mammospheres, a method known to enrich for cells with CSC-properties. An unbiased, comparative global proteomic analysis using label-free mass spectrometry was performed on the patient tumor tissues and corresponding PDX tumors and mammospheres. Good concordance between the proteome profiles of patient tumor tissue and corresponding PDX tumors was observed. However, lower abundance of immune- and extracellular matrix-related proteins and higher abundance of proteins associated with cell-to-cell adhesion including desmosome proteins and β-catenin were observed in PDX versus patient tumors. Interestingly, analysis of proteins elevated in mammospheres vs. PDX tumors identified an enrichment of proteins associated with de novo cholesterol synthesis. The clinical relevance of increased cholesterol biosynthesis protein expression was verified in a large gene expression data set of clinical breast cancers showing correlation with shorter relapse-free survival. RNA interference and chemical inhibition of the cholesterol biosynthesis pathway reduced mammosphere formation and growth of CSCs derived from PDX tumors and cancer cell lines. Our findings identify the cholesterol biosynthesis pathway as central for CSC growth and a potential therapeutic target for CSC as well as providing an additional mechanistic explanation for the observed benefit of statins in breast cancer treatment.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell

DISEASE(S): Breast Cancer

SUBMITTER: Brian Hood

LAB HEAD: Henrik J. Ditzel

PROVIDER: PXD011222 | Pride | 2019-07-02

REPOSITORIES: Pride

ACCESS DATA

Publications

Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome.

Ehmsen Sidse S Pedersen Martin H MH Wang Guisong G Terp Mikkel G MG Arslanagic Amina A Hood Brian L BL Conrads Thomas P TP Leth-Larsen Rikke R Ditzel Henrik J HJ

Cell reports 20190601 13

Tumor eradication may be greatly improved by targeting cancer stem cells (CSCs), as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed patient-derived xenograft tumors (PDXs) from ER<sup>-</sup> breast cancers from which we isolated mammospheres that are enriched for CSCs. Comparative global proteomic analysis was performed on patient tumor tissues and corresponding PDXs and mammospheres. Mammospheres exhibited increased expression of p ...[more]

PMID: 31242424

Similar Datasets

Project description:Osteosarcoma (OS) and Ewing’s sarcoma (EW) are the two most common pediatric solid tumors, after brain tumors. Multimodal treatments have significantly improved prognosis in localized disease but outcome is still poor in metastatic patients, for whom therapeutic options are often inadequate. Preclinical drug testing to identify promising treatment options that match the molecular make-up of these tumors is hampered by the lack of appropriate and molecularly well-characterized patient-derived models. To address this need, a panel of patient-derived xenografts (PDX) was established by subcutaneous implantation of fresh, surgically resected OS and EW tumors in NSG mice. Tumors were re-transplanted to next mice generations and fragments were collected for histopathological and molecular characterization. A model was considered established after observing stable histological and molecular features for at least three passages. To evaluate the similarity of the model with primary tumor, we performed a global gene expression profiling and tissue microarrays (TMA), to assess tumor specific biomarkers on tissues from OS/EW tumors and their PDXs (1st and 3rd passage). Moreover, we verified the feasibility of these models for preclinical drug testing. We implanted 61 OS and 29 EW samples: 14/38 (37%) primary OS and 9/23 (39%) OS lung metastases successfully engrafted; while among EW, 5/26 (19%) primary samples and 1/3 (33%) metastases were established. Comparison between patient samples and PDXs, highlighted that histology and genetic characteristics of PDXs were stable and maintained over passages. In particular, correlative analysis between OS and EW samples and their PDXs was extremely high (Pearson’s r range r=0.94-0.96), while patient-derived primary cultures displayed reduced correlation with human samples (r=0.90-0.93), indicating that in vitro adaptation superimpose molecular alterations that create genetic diversion from original tumors. No significant differentially expressed gene profile was observed from the comparison between EW samples and PDXs (fold change > 2, adjusted p <0.05 at paired t-test). In OS, the comparison between OS patient-derived tumors and PDX indicated differences in 397 genes, mostly belonging to immune system functional category. This is in line with the idea that human immune cells are gradually replaced by murine counterparts upon engraftment in the mouse. As proof-of concept, two EW PDX and one OS PDX have been treated with conventional and innovated drugs to test their value in terms of drug-sensitivity prediction. Overall, our study indicated that PDX models maintained the histological and genetic markers of the tumor samples and represent reliable models to test sensitivity to novel drug associations.

Dataset Information

Increased cholesterol biosynthesis identified as a key feature and a therapeutic target of cancer stem cells as revealed by proteomic comparison of clinical breast cancer tissue and corresponding patient-derived xenografts and mammospheres

Publications

Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure