Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery
Open accessAbstract
Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored. Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.
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ZEB2 activation is a key downstream event in the reprogramming of CMS2 cancer cells into a CMS4 subtype in response to visceral adipose-derived factors, through a STAT3-miR200 axis.
“ZEB2 activation was also depicted as a key downstream event in the reprogramming of CMS2 cancer cells into a CMS4 subtype in response to visceral adipose-derived factors, through a STAT3-miR200 axis (21).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [21]
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- Authors
- Di Franco, S., Bianca, P., Sardina, D. S., Turdo, A., Gaggianesi, M., Veschi, V., Nicotra, A., Mangiapane, L. R., Lo Iacono, M., Pillitteri, I., van Hooff, S., Martorana, F., Motta, G., Gulotta, E., Lentini, V. L., Martorana, E., Fiori, M. E., Vieni, S., Bongiorno, M. R., Giannone, G., Giuffrida, D., Memeo, L., Colarossi, L., Mare, M., Vigneri, P., Todaro, M., De Maria, R., Medema, J. P., & Stassi, G.
- Affiliations
- University of Palermo (IT)
- University of Catania (IT)
- Ospedale Vincenzo Cervello (IT)
- Istituto Superiore di Sanità (IT)
- University of Messina (IT)
- Amsterdam University Medical Centers (NL)
- Corresponding author
- Stassi, Giorgio
- ORCID
- Di Franco, Simone
- Bianca, Paola
- Sardina, Davide Stefano
- Turdo, Alice
- Gaggianesi, Miriam
- Veschi, Veronica
- Nicotra, Annalisa
- Mangiapane, Laura Rosa
- Lo Iacono, Melania
- Pillitteri, Irene
- Martorana, Federica
- Motta, Gianmarco
- Lentini, Vincenzo Luca
- Martorana, Emanuele
- Fiori, Micol Eleonora
- Vieni, Salvatore
- Bongiorno, Maria Rita
- Giuffrida, Dario
- Memeo, Lorenzo
- Colarossi, Lorenzo
- Vigneri, Paolo
- Todaro, Matilde
- Medema, Jan Paul
- Stassi, Giorgio
- Venue
- Nature Communications
- Published
- 2021-08-18
- Volume
- 12
- Issue
- 1
- Pages
- 5006-5006
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8373975
- OpenAlex
- W3194895625
- Cited by
- 80
- References
- 75
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 20 · 2023: 14 · 2022: 18 · 2021: 3
- FWCI
- 5.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS UniPA (University of Palermo) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, cc-by)
- Funders
- Ministero dell'Istruzione, dell'Università e della Ricerca (PRIN 2017WNKSLR)
- Associazione Italiana per la Ricerca sul Cancro (AIRC 5x1000 9979, AIRC IG 21445)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- colorectal cancer, obesity, adipose-derived stem cells, visceral adipose tissue, cancer stem cells, metastasis, tumor microenvironment, interleukin-6, hepatocyte growth factor, nerve growth factor, neurotrophin-3, neurotrophins, STAT3, miR-200a, ZEB2, epithelial-mesenchymal transition, CD44v6, consensus molecular subtypes, vasculogenesis
- MeSH terms
- Zinc Finger E-box Binding Homeobox 2, Adipose Tissue, Animals, Colonic Neoplasms, Humans, Male, Neoplasm Metastasis, Stem Cells, Neoplastic Stem Cells, Interleukin-6, Mice, SCID, Hepatocyte Growth Factor, MicroRNAs, Mice, Stem Cell Niche, Cellular Reprogramming
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 ›
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