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The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYCO65 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYOV-amplified neuroblastoma via multiple mechanisms. CDK9--a component of the transcription elongation complex P-TEFb--bound to the MYCAf-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCAf-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYCO65. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYCO65. CYCO65, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCAf-amplified neuroblastoma., Introduction The prominent role of Myc family protooncogene transcription factors (TFs) (MYC, MYCN, MYCL) in the genesis of adult and childhood cancers makes these TFs attractive targets for drug discovery [...]

The tumor-suppressive role of trefoil factor family (TFF) members in gastric carcinogenesis has been suggested, but their significance and mechanisms in other digestive diseases remain elusive. To clarify the role of TFF1 in pancreatic carcinogenesis, we performed IHC on human samples, transfected siRNA against TFF1 into pancreatic cancer cell lines, and employed mouse models in which PanIN development and loss of TFF1 occur simultaneously. In human samples, the expression of TFF1 was specifically observed in pancreatic intraepithelial neoplasm (PanIN), but was frequently lost in the invasive component of pancreatic ductal adenocarcinoma (PDAC). When the expression of TFF1 was suppressed in vitro, pancreatic cancer cell lines showed enhanced invasive ability and features of epithelial-mesenchymal transition (EMT), including upregulated Snail expression. TFF1 expression was also observed in PanIN lesions of Pdx-1 Cre; [LSL-KRAS.sup.G12D] (KC) mice, a model of pancreatic cancer, and loss of TFF1 in these mice resulted in the expansion of PanIN lesions, an EMT phenotype in PanIN cells, and an accumulation of cancer- associated fibroblasts (CAFs), eventually resulting in the development of invasive adenocarcinoma. This study indicates that the acquisition of TFF1 expression is an early event in pancreatic carcinogenesis and that TFF1 might act as a tumor suppressor to prevent EMT and the invasive transformation of PanIN., Introduction Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide (1), partly because it is usually diagnosed at an advanced stage, with metastasis and extensive tumor invasion [...]

Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand these potentially opposing functions by interrogating functional relationships among CAF subtypes, their mediators, desmoplasia, and tumor growth in a wide range of tumor types metastasizing to the liver, the most common organ site for metastasis. Depletion of hepatic stellate cells (HSC), which represented the main source of CAF in mice and patients in our study, or depletion of all CAF decreased tumor growth and mortality in desmoplastic colorectal and pancreatic metastasis but not in nondesmoplastic metastatic tumors. Single-cell RNA-Seq in conjunction with CellPhoneDB ligand-receptor analysis, as well as studies in immune cell- depleted and HSC-selective knockout mice, uncovered direct CAF-tumor interactions as a tumor-promoting mechanism, mediated by myofibroblastic CAF-secreted (myCAF-secreted) hyaluronan and inflammatory CAF-secreted (iCAF-secreted) HGF. These effects were opposed by myCAF-expressed type I collagen, which suppressed tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction by type I collagen opposes the overall tumor-promoting effects of CAF, thus providing a mechanistic explanation for their dual functions in cancer. Therapeutic targeting of tumor-promoting CAF mediators while preserving type I collagen may convert CAF from tumor promoting to tumor restricting., Introduction Metastasis is the main cause of mortality in the majority of patients with tumors, and the liver represents the main organ site for metastatic seeding and growth (1-4). Pancreatic [...]