title: Collagen-rich stroma in aggressive colon tumors induces mesenchymal gene expression and tumor cell invasion.
abstract: Gene expression-based classification systems have identified an aggressive colon cancer subtype with mesenchymal features, possibly reflecting epithelial-to-mesenchymal transition (EMT) of tumor cells. However, stromal fibroblasts contribute extensively to the mesenchymal phenotype of aggressive colon tumors, challenging the notion of tumor EMT. To separately study the neoplastic and stromal compartments of colon tumors, we have generated a stroma gene filter (SGF). Comparative analysis of stromahighand stromalowtumors shows that the neoplastic cells in stromahightumors express specific EMT drivers (ZEB2, TWIST1, TWIST2) and that 98% of differentially expressed genes are strongly correlated with them. Analysis of differential gene expression between mesenchymal and epithelial cancer cell lines revealed that hepatocyte nuclear factor 4α (HNF4α), a transcriptional activator of intestinal (epithelial) differentiation, and its target genes are highly expressed in epithelial cancer cell lines. However, mesenchymal-type cancer cell lines expressed only part of the mesenchymal genes expressed by tumor-derived neoplastic cells, suggesting that external cues were lacking. We found that collagen-I dominates the extracellular matrix in aggressive colon cancer. Mimicking the tumor microenvironment by replacing laminin-rich Matrigel with collagen-I was sufficient to induce tumor-specific mesenchymal gene expression, suppression of HNF4α and its target genes, and collective tumor cell invasion of patient-derived colon tumor organoids. The data connect collagen-rich stroma to mesenchymal gene expression in neoplastic cells and to collective tumor cell invasion. Targeting the tumor-collagen interface may therefore be explored as a novel strategy in the treatment of aggressive colon cancer.
authors.affiliation: Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: T T
authors.initials: TT
authors.lastname: Vellinga
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Surgery, Spaarne Gasthuis, Haarlem, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: den Uil
authors.affiliation: Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: I H B
authors.initials: IH
authors.lastname: Rinkes
authors.affiliation: Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Marvin
authors.affiliation: Department Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Ponsioen
authors.affiliation: Department Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Alvarez-Varela
authors.affiliation: Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Fatrai
authors.affiliation: Department Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Scheele
authors.affiliation: Department of Oncogenomics, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: D A
authors.initials: DA
authors.lastname: Zwijnenburg
authors.affiliation: Department Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Snippert
authors.affiliation: Center of Experimental and Molecular Medicine, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Vermeulen
authors.affiliation: Center of Experimental and Molecular Medicine, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: Medema
authors.affiliation: Department of Surgery, Spaarne Gasthuis, Haarlem, The Netherlands.
authors.forename: H B
authors.initials: HB
authors.lastname: Stockmann
authors.affiliation: Center of Experimental and Molecular Medicine, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Koster
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: R J A
authors.initials: RJ
authors.lastname: Fijneman
authors.affiliation: Department of Surgery, Spaarne Gasthuis, Haarlem, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: de Rooij
authors.affiliation: Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: O
authors.initials: O
authors.lastname: Kranenburg
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D003094:Collagen