Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery

Simone Di Franco, Paola Bianca, Davide Stefano Sardina, Alice Turdo, Miriam Gaggianesi, Veronica Veschi, Annalisa Nicotra, Laura Rosa Mangiapane, Melania Lo Iacono, Irene Pillitteri, Sander Hooff, Federica Martorana, Gianmarco Motta, Eliana Gulotta, Vincenzo Luca Lentini, Emanuele Martorana, Micol Eleonora Fiori, Salvatore Vieni, Maria Rita Bongiorno, Giorgio Giannone, Dario Giuffrida, Lorenzo Memeo, Lorenzo Colarossi, Marzia Mare, Paolo Vigneri, Matilde Todaro, Ruggero De Maria, Jan Paul Medema and Giorgio Stassi ()
Additional contact information
Simone Di Franco: University of Palermo
Paola Bianca: University of Palermo
Davide Stefano Sardina: University of Palermo
Alice Turdo: University of Palermo
Miriam Gaggianesi: University of Palermo
Veronica Veschi: University of Palermo
Annalisa Nicotra: University of Palermo
Laura Rosa Mangiapane: University of Palermo
Melania Lo Iacono: University of Palermo
Irene Pillitteri: University of Palermo
Sander Hooff: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam
Federica Martorana: University of Catania
Gianmarco Motta: University of Catania
Eliana Gulotta: Reconstructive Plastic Surgery, ARNAS Ospedali Civico Di Cristina e Benfratelli
Vincenzo Luca Lentini: Pathology Unit, Ospedali Riuniti Villa Sofia-Cervello
Emanuele Martorana: IOM (Mediterranean Institute of Oncology) Ricerca, Viagrande
Micol Eleonora Fiori: Istituto Superiore di Sanità
Salvatore Vieni: University of Palermo
Maria Rita Bongiorno: University of Palermo
Giorgio Giannone: Mediterranean Institute of Oncology, Viagrande
Dario Giuffrida: Mediterranean Institute of Oncology, Viagrande
Lorenzo Memeo: Mediterranean Institute of Oncology, Viagrande
Lorenzo Colarossi: Mediterranean Institute of Oncology, Viagrande
Marzia Mare: Mediterranean Institute of Oncology, Viagrande
Paolo Vigneri: University of Catania
Matilde Todaro: University of Palermo
Ruggero De Maria: Istituto di Patologia Generale, Università Cattolica del Sacro Cuore
Jan Paul Medema: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam
Giorgio Stassi: University of Palermo

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25333-9

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