A three-dimensional engineered tumour for spatial snapshot analysis of cell metabolism and phenotype in hypoxic gradients
Open accessAbstract
The profound metabolic reprogramming that occurs in cancer cells has been investigated primarily in two-dimensional cell cultures, which fail to recapitulate spatial aspects of cell-to-cell interactions as well as tissue gradients present in three-dimensional (3D) tumours. Here, we describe an engineered model to assemble 3D tumours by rolling a scaffold-tumour composite strip. By unrolling the strip, the model can be rapidly disassembled for snap-shot analysis, allowing spatial mapping of cell metabolism in concert with cell phenotype. We also show that the establishment of oxygen gradients within samples are shaped by oxygen-dependent signalling pathways, as well as the consequential variations in cell growth, response to hypoxic gradients extending from normoxia to severe hypoxia, and therapy responsiveness, are consistent with tumours in vivo. Moreover, by using liquid chromatography tandem mass spectrometry, we mapped cellular metabolism and identified spatially defined metabolic signatures of cancer cells to reveal both known and novel metabolic responses to hypoxia.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Cell metabolism is deregulated in the absence of HIF.
“They demonstrated the change in 88 metabolites during cellular adaptation to hypoxia gradient and found that cell metabolism was deregulated in the absence of HIF.”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [216]
The 'Metabolomic signature mapping in 3D' section says 88 metabolites were analyzed, but only 23 showed a significant correlation with hypoxia in control cells; it does not report changes in all 88. The 'HIF-dependent and HIF-independent metabolic signatures' section reports changes in several metabolites in HIF-knockdown cells, but the Outlook says changes in glycolysis and mitochondrial metabolism were largely HIF-independent. Thus the broad statement that cell metabolism was deregulated in the absence of HIF overstates the findings. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThese 3D tissue structures generated a hypoxic environment in the inner core, greatly recapitulating in vivo spatial oxygen distribution.
“They rebuilt largely in vitro 3D tumor tissues and were able to generate a hypoxic environment in the inner core, which greatly recapitulated in vivo spatial oxygen distribution.”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [216]
Some recent works adopted 3D tissue structures to reconstitute the oxygen gradient in the tumor.
“Different from these engineering approaches, some recent works adopted 3D tissue structures to reconstitute the oxygen gradient in the tumor [215, 216].”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [216]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 30 · Cited by 132
- Authors
- Rodenhizer, D., Gaude, E., Cojocari, D., Mahadevan, R., Frezza, C., Wouters, B. G., & McGuigan, A. P.
- Affiliations
- University of Toronto (CA)
- University of Cambridge (GB)
- University Health Network (CA)
- Corresponding author
- McGuigan, Alison P.
- ORCID
- Venue
- Nature Materials
- Published
- 2015-11-23
- Volume
- 15
- Issue
- 2
- Pages
- 227-234
- ISSN
- 1476-1122 (ISSN-L)
- 1476-4660
- PMC
- PMC5214740
- OpenAlex
- W2265649595
- Semantic Scholar
- 5d2ff9c076a4898b053b0b4fed1d91ede7c410d3
- Cited by
- 132
- References
- 30
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 9 · 2023: 12 · 2022: 13 · 2021: 15 · 2020: 17 · 2019: 19 · 2018: 16 · 2017: 16 · 2016: 6
- FWCI
- 4.19
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-01-22)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Materials (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Apollo (University of Cambridge) (acceptedVersion)
- TSpace (University of Toronto) (submittedVersion)
- Funders
- University of Toronto
- Canadian Institutes of Health Research (201592, 97985_1, 142312_1)
- Natural Sciences and Engineering Research Council of Canada (RGPIN-314056)
- Medical Research Council (MC_UU_12022/6)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- hypoxia, oxygen gradients, cancer metabolism, metabolic reprogramming, cell-cell interactions, cell phenotype, tumor oxygenation
- MeSH terms
- Antibiotics, Antineoplastic, Doxorubicin, Humans, Neoplasms, Oxygen, Signal Transduction, Gene Expression Regulation, Neoplastic, Tissue Engineering, Cell Line, Tumor, Cell Proliferation, Hypoxia-Inducible Factor 1, Tissue Scaffolds
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
