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PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [ChIP-seq]

ABSTRACT: Purpose: This study sought to identify signaling pathways that modulate β-catenin function in desmoid cells, affecting natural history and sorafenib response. Experimental Design: In vitro experiments utilized primary desmoid cell lines to examine interaction of β-catenin signaling with other pathways. Relevance of in vitro results was assessed in surgical specimens and Alliance trial A091105 correlative biopsies. Results: CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α. Expression of hypoxia-associated genes clustered desmoids separately from normal mesenchymal tissue. ChIP-seq identified ABL1 as a β-catenin transcriptional target that modulated HIF1α protein expression and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1 inhibited the ability of desmoid cells to induce VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRβ signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by activation of PDGF signaling. Reduction in PDGFRβ and c-Abl phosphorylation was commonly observed in samples from patients after treatment with sorafenib; baseline samples in patients with greater drug response tended to have higher baseline PDGFRβ/c-Abl pathway activation. Conclusions: The β-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α protein expression in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244160 | GEO | 2023/11/01

REPOSITORIES: GEO

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Project description:Desmoid tumors (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumors arise in individuals affected by either familial adenomatous polyposis (FAP) or hereditary desmoid disease (HDD) carrying germline mutations in APC. Most non-FAP (sporadic) desmoids carry somatic mutations in the beta-catenin gene. Previous studies identified losses on 5q and 6q, and gains on 8q and 20q as recurrent genetic changes in desmoids. However, virtually all genetic changes were derived from sporadic tumors. To investigate the somatic alterations in FAP-associated desmoids and to compare them with changes occurring in sporadic tumors, we analyzed 17 FAP-associated and 38 sporadic desmoids for copy number abnormalities (CNAs) by means of array comparative genomic hybridization and multiple ligation-dependent probe amplification. Overall, the desmoids displayed only a limited number of genetic changes, occurring in 44% of cases. Common gains at 8q (7%) and 20q (5%) were almost exclusively found in sporadic tumors. Frequent common losses were observed within a 700 kb region at 5q22.2, comprising the APC gene (11%), in a 2 Mb region at 6p21.2-p21.1 (15%), and in a relatively large region at 6q15-q23.3 (20%). The FAP-associated desmoids displayed a significantly higher frequency of CNAs (59%) than the sporadic tumors (37%). As predicted by the APC germline mutations among these patients, a relatively high percentage (29%) of the FAP-associated desmoids showed loss of the APC region at 5q22.2, which was infrequently (3%) seen among sporadic tumors. Our data suggest that loss of region 6q15-q16.2 is an important event in FAP-associated as well as sporadic desmoids, most likely of relevance for desmoid tumor progression. Fifty-three fresh frozen tumor samples were collected at four institutes: Center for Human Genetics, University of Leuven, Belgium (21 samples); INSERM U674, Fondation Jean Dausset-CEPH, Paris, France (15 samples); Hospital for Sick Children, Toronto, Canada (13 samples); and the Italian Registry of Hereditary Colorectal Cancer (Dr. L. Bertario, 4 samples). In addition, DNA of two fresh frozen tumors, HDD-H of patient III:2 and HDD-I of patient III:6, of our hereditary desmoids disease (HDD) family10 was available (Table 1). In this family, multifocal desmoid tumors were inherited as an autosomal dominant trait, and HDD segregated with a 3' APC mutation at codon 1924. For the latter reason, they were classified as FAP tumors in this study. Three FAP tumors were derived from a family with 2 relatives in the study (D15-1 and D15-2 of a male patient and D16 of his sister). Colonic polyposis had been observed in 12 FAP patients, not in the 2 HDD-FAP patients and not in patient D15. The germline APC mutation was known in 14 of 17 FAP-associated tumors. In 28 of 38 non-FAP-associated desmoid tumors, the beta-catenin gene (CTNNB1) mutation in exon 3 was known and in 1 of 38 tumors an APC mutation was present (data not shown). The remaining tumors were characterized as FAP or non-FAP based on clinical data and positivity of tumor cells upon immunostaining for beta-catenin. DNA was extracted from the tumor samples according to standard methods.

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PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [ChIP-seq]

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