6533b872fe1ef96bd12d433b
RESEARCH PRODUCT
Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery.
Miriam GaggianesiJan Paul MedemaLaura Rosa MangiapaneMarzia MareDavide Stefano SardinaAlice TurdoSander R. Van HooffDario GiuffridaMicol E. FioriSalvatore VieniMaria Rita BongiornoPaolo VigneriIrene PillitteriVeronica VeschiSimone Di FrancoEliana GulottaMatilde TodaroLorenzo MemeoMelania Lo IaconoRuggero De MariaLorenzo ColarossiVincenzo Luca LentiniPaola BiancaAnnalisa NicotraGianmarco MottaGiorgio GiannoneEmanuele MartoranaGiorgio StassiFederica Martoranasubject
MaleCancer microenvironmentobesityStromal cellColorectal cancerScienceSettore MED/50 - Scienze Tecniche Mediche ApplicateGeneral Physics and AstronomyAdipose tissueMice SCIDSCIDmetastasis.General Biochemistry Genetics and Molecular BiologyArticleMiceVasculogenesisSettore MED/04 - PATOLOGIA GENERALEmedicineAnimalsHumansNeoplasm MetastasisStem Cell NicheZinc Finger E-box Binding Homeobox 2Tumor microenvironmentMultidisciplinarybusiness.industryHepatocyte Growth FactorInterleukin-6Stem CellsQadipose stromal cellCancerCD44v6General Chemistrymedicine.diseaseCellular ReprogrammingColorectal cancerMicroRNAsAdipose TissueCancer cellColonic NeoplasmsCancer researchNeoplastic Stem Cellsconsensus molecular subtypeStem cellSettore MED/46 - Scienze Tecniche Di Medicina Di Laboratoriobusinessdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-12-01 | Nature communications |