SUMMARY Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era.

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Bone metastases remain as a serious health concern because of limited therapeutic options. Here, we report that crosstalk between ROR1-HER3 and the Hippo-YAP pathway promotes breast cancer bone metastasis in a long noncoding RNA-dependent fashion. Mechanistically, the orphan receptor tyrosine kinase ROR1 phosphorylates HER3 at a previously unidentified site Tyr1307, upon neuregulin stimulation, independently of other ErbB family members. p-HER3 Tyr1307 recruits the LLGL2-MAYA-NSUN6 RNA-protein complex to methylate Hippo/MST1 at Lys59. This methylation leads to MST1 inactivation and activation of YAP target genes in tumor cells, which elicits osteoclast differentiation and bone metastasis. Furthermore, increased ROR1, p-HER3 Tyr1307 and MAYA levels correlate with tumor metastasis and unfavorable outcomes. Our data provide insights into the mechanistic regulation and linkage of the ROR1-HER3 and Hippo-YAP pathway in cancer-specific context, and also imply valuable therapeutic targets for bone metastasis and possible therapy-resistant tumors.

SUMMARY Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes—modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility.

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Purpose Recent studies show that colorectal tumors with high microsatellite instability (MSI-H) have increased immunogenicity and response to immunotherapy compared to microsatellite stable (MSS) tumors. It is not yet clear if MSI-H endometrial cancer (EC) may also benefit from these therapies. It is also unknown whether immune response is equivalent in MSI-H EC with sporadic or inherited Lynch syndrome origins. Experimental Design Multiplexed fluorescent immunohistochemistry (IHC) was used to compare matched MSI-H (n=60) and MSS (n=96) EC specimens by evaluating immune cell populations in tumor and stroma compartments. Sporadic MSI-H and Lynch syndrome-associated (LS) MSI-H EC were also directly compared. Results Increased immune cells were present in stroma of MSI-H EC compared to MSS, including granzyme B+ cells, activated cytotoxic T lymphocytes (CTLs, CD8+granzyme B+), and PD-L1+ cells. Granzyme B+ cells and activated CTLs were also increased in the tumor compartment of MSI-H ECs. Comparing sporadic and LS MSI-H EC showed distinct differences in immune cell populations, indicating that mechanisms underlying microsatellite instability alter immune response. Specifically, LS MSI-H EC showed increased CD8+ cells and activated CTLs in stroma, with reduced macrophages in stroma and tumor compared to sporadic MSI-H. Sporadic MSI-H had increased PD-L1+ macrophages in stroma and tumor compared to LS MSI-H EC. Conclusions MSI-H EC has increased immune cell infiltration compared to MSS EC and the hereditary or sporadic origin of microsatellite instability impacts immune response. Clinical trials to determine the role of immunotherapy in patients with MSI-H EC must evaluate Lynch-related and sporadic MSI-H tumors separately.