SummaryThe metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to highly penetrant metastasis (100% metastasis; with >80% liver metastases) in KrasG12D-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.

BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ∼80% of BRAF V600 -mutant melanoma patients that almost uniformly precedes the emergence of resistance. Here we used a mouse model of melanoma in which melanocyte-specific expression of Braf V618E (analogous to the human BRAF V600E mutation) led to the development of skin hyperpigmentation and nevi, as well as melanoma formation with incomplete penetrance. Sleeping Beauty insertional mutagenesis in this model led to accelerated and fully penetrant melanomagenesis and synchronous tumor formation. Treatment of Braf V618E transposon mice with the BRAF inhibitor PLX4720 resulted in tumor regression followed by relapse. Analysis of transposon insertions identified eight genes including Braf, Mitf, and ERas (ES-cell expressed Ras) as candidate resistance genes. Expression of ERAS in human melanoma cell lines conferred resistance to PLX4720 and induced hyperphosphorylation of AKT (v-akt murine thymoma viral oncogene homolog 1), a phenotype reverted by combinatorial treatment with PLX4720 and the AKT inhibitor MK2206. We show that ERAS expression elicits a prosurvival signal associated with phosphorylation/inactivation of BAD, and that the resistance of hepatocyte growth factor-treated human melanoma cells to PLX4720 can be reverted by treatment with the BAD-like BH3 mimetic ABT-737. Thus, we define a role for the AKT/BAD pathway in resistance to BRAF inhibition and illustrate an in vivo approach for finding drug resistance genes. melanoma | drug resistance | BRAF inhibitors | mouse models T he discovery that ∼50-60% of melanomas carry BRAF V600E point mutations (1) prompted the generation of compounds specifically targeting this hyperactive mutated kinase. One such compound, PLX4032, has shown unprecedented therapeutic efficacy in clinical trials and was therefore FDA-approved for clinical therapy under the name vemurafenib. Despite its remarkable efficacy, almost all patients receiving BRAF inhibitor treatment relapsed after weeks to months of therapy (2-5). Acquired resistance to BRAF inhibitors has since been a major focus of research and two major paths to resistance have emerged: MAPK-dependent and MAPK-independent mechanisms. MAPK-dependent mechanisms primarily involve reactivation of the MAPK pathway to substitute for the inhibition of BRAF V600E. This may be achieved through mechanisms including expression of alternative splicing forms of BRAF V600E

In this paper, we propose a Blockchain-based infrastructure to support security-and privacy-oriented spatio-temporal smart contract services for the sustainable Internet of Things (IoT)-enabled sharing economy in mega smart cities. The infrastructure leverages cognitive fog nodes at the edge to host and process offloaded geo-tagged multimedia payload and transactions from a mobile edge and IoT nodes, uses AI for processing and extracting significant event information, produces semantic digital analytics, and saves results in Blockchain and decentralized cloud repositories to facilitate sharing economy services. The framework offers a sustainable incentive mechanism, which can potentially support secure smart city services, such as sharing economy, smart contracts, and cyber-physical interaction with Blockchain and IoT. Our unique contribution is justified by detailed system design and implementation of the framework. INDEX TERMS Sharing economy, cognitive processing at the edge, mobile edge computing, Blockchain, smart city.

A major challenge for cancer genetics is to determine which low frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers to identify novel drivers and find inactivating mutations in the homeodomain transcription factor CUX1 (cut-like homeobox 1) in ~1-5% of tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss. In parallel, we validate CUX1 as a bona fide tumor suppressor using mouse transposon-mediated insertional mutagenesis and Drosophila cancer models. We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth, while exposing susceptibility to PI3K-AKT inhibition. Thus, our complementary approaches identify CUX1 as a new pan-driver of tumorigenesis and uncover a potential strategy for treating CUX1-mutant tumors.

Senescent cells may promote tumour progression through the activation of a senescence-associated secretory phenotype (SASP), whether these cells are capable of initiating tumourigenesis in vivo is not known. Expression of oncogenic β-catenin in Sox2+ young adult pituitary stem cells leads to formation of clusters of stem cells and induction of tumours resembling human adamantinomatous craniopharyngioma (ACP), derived from Sox2− cells in a paracrine manner. Here, we uncover the mechanisms underlying this paracrine tumourigenesis. We show that expression of oncogenic β-catenin in Hesx1+ embryonic precursors also results in stem cell clusters and paracrine tumours. We reveal that human and mouse clusters are analogous and share a common signature of senescence and SASP. Finally, we show that mice with reduced senescence and SASP responses exhibit decreased tumour-inducing potential. Together, we provide evidence that senescence and a stem cell-associated SASP drive cell transformation and tumour initiation in vivo in an age-dependent fashion.