Reducing MYC's transcriptional footprint unveils a good prognostic gene signature in melanoma.

MYC's key role in oncogenesis and tumor progression has long been established for most human cancers. In melanoma, its deregulated activity by amplification of 8q24 chromosome or by upstream signaling coming from activating mutations in the RAS/RAF/MAPK pathway-the most predominantly mutated pathway in this disease-turns MYC into not only a driver but also a facilitator of melanoma progression, with documented effects leading to an aggressive clinical course and resistance to targeted therapy. Here, by making use of Omomyc, the most characterized MYC inhibitor to date that has just successfully completed a phase I clinical trial, we show for the first time that MYC inhibition in melanoma induces remarkable transcriptional modulation, resulting in severely compromised tumor growth and a clear abrogation of metastatic capacity independently of the driver mutation. By reducing MYC's transcriptional footprint in melanoma, Omomyc elicits gene expression profiles remarkably similar to those of patients with good prognosis, underlining the therapeutic potential that such an approach could eventually have in the clinic in this dismal disease.

MYC Inhibition Halts Metastatic Breast Cancer Progression by Blocking Growth, Invasion, and Seeding.

MYC's role in promoting tumorigenesis is beyond doubt, but its function in the metastatic process is still controversial. Omomyc is a MYC dominant negative that has shown potent antitumor activity in multiple cancer cell lines and mouse models, regardless of their tissue of origin or driver mutations, by impacting on several of the hallmarks of cancer. However, its therapeutic efficacy against metastasis has not been elucidated yet. Here we demonstrate for the first time that MYC inhibition by transgenic Omomyc is efficacious against all breast cancer molecular subtypes, including triple-negative breast cancer, where it displays potent antimetastatic properties both in vitro and in vivo. Importantly, pharmacologic treatment with the recombinantly produced Omomyc miniprotein, recently entering a clinical trial in solid tumors, recapitulates several key features of expression of the Omomyc transgene, confirming its clinical applicability to metastatic breast cancer, including advanced triple-negative breast cancer, a disease in urgent need of better therapeutic options. Significance: While MYC role in metastasis has been long controversial, this manuscript demonstrates that MYC inhibition by either transgenic expression or pharmacologic use of the recombinantly produced Omomyc miniprotein exerts antitumor and antimetastatic activity in breast cancer models in vitro and in vivo, suggesting its clinical applicability.

The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets.

The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional target, impairs sustained tumor expansion and ß-cell dedifferentiation in a mouse model of Myc-driven insulinoma, allows pancreatic islets to maintain their physiological structure and affects Myc-related global gene expression. Importantly, Wnt signaling inhibition in Fzd9-competent mice largely recapitulates the suppression of proliferation caused by Fzd9 deficiency upon Myc activation. Together, our results indicate that the Wnt signaling receptor Fzd9 is essential for Myc-induced tumorigenesis in pancreatic islets.

Vitamin D receptor deficiency enhances Wnt/ß-catenin signaling and tumor burden in colon cancer.

Aberrant activation of the Wnt/ß-catenin pathway is critical for the initiation and progression of most colon cancers. This activation provokes the accumulation of nuclear ß-catenin and the induction of its target genes. Apc(min/+) mice are the most commonly used model for colon cancer. They harbor a mutated Apc allele and develop intestinal adenomas and carcinomas during the first months of life. This phenotype is caused by the mutation of the second Apc allele and the consequent accumulation of nuclear ß-catenin in the affected cells. Here we describe that vitamin D receptor (VDR) is a crucial modulator of nuclear ß-catenin levels in colon cancer in vivo. By appropriate breeding of Apc(min/+) mice and Vdr(+/-) mice we have generated animals expressing a mutated Apc allele and two, one, or none Vdr wild type alleles. Lack of Vdr increased the number of colonic Aberrant Crypt Foci (ACF) but not that of adenomas or carcinomas in either small intestine or colon. Importantly, colon ACF and tumors of Apc(min/+)Vdr(-/-) mice had increased nuclear ß-catenin and the tumors reached a larger size than those of Apc(min/+)Vdr(+/+). Both ACF and carcinomas in Apc(min/+)Vdr(-/-) mice showed higher expression of ß-catenin/TCF target genes. In line with this, VDR knock-down in cultured human colon cancer cells enhanced ß-catenin nuclear content and target gene expression. Consistently, VDR depletion abrogated the capacity of 1,25(OH)(2)D(3) to promote the relocation of ß-catenin from the nucleus to the plasma membrane and to inhibit ß-catenin/TCF target genes. In conclusion, VDR controls the level of nuclear ß-catenin in colon cancer cells and can therefore attenuate the impact of oncogenic mutations that activate the Wnt/ß-catenin pathway.