Summary Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members whose expression is elevated in many diseases, including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). We show that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the classic gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signaling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated upon receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signaling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.

Summary Interleukin-17A (IL-17A) is a proinflammatory cytokine linked to rapid malignant progression of colorectal cancer (CRC) and therapy resistance. IL-17A exerts its pro-tumorigenic activity through its type A receptor (IL-17RA). However, how IL-17RA engagement promotes colonic tumorigenesis is unknown, as IL-17RA is expressed in many cell types in the tumor microenvironment, including hematopoietic, fibroblastoid and epithelial cells. Here we show that IL-17RA signals directly within transformed colonic epithelial cells (enterocytes) to promote early tumor development. IL-17RA engagement activates ERK, p38 MAPK and NF-κB signaling and promotes the proliferation of tumorigenic enterocytes who just lost expression of the APC tumor suppressor. Although IL-17RA signaling also controls production of IL-6, this mechanism makes only a partial contribution to colonic tumorigenesis. Combined treatment with chemotherapy, which induces IL-17A expression, and an IL-17A neutralizing antibody enhanced the therapeutic responsiveness of established colon tumors. These findings establish IL-17A and IL-17RA as therapeutic targets in colorectal cancer.

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Metastatic spread is the leading cause of cancer mortality. Breast cancer (BCa) metastatic recurrence can happen years after removal of the primary tumor. Here we show that Ubc13, an E2 enzyme that catalyzes K63-linked protein polyubiquitination, is largely dispensable for primary mammary tumor growth but is required for metastatic spread and lung colonization by BCa cells. Loss of Ubc13 inhibited BCa growth and survival only at metastatic sites. Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFβ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa.ubiquitination-mediated signaling | pre-clinical studies B reast cancer (BCa) is the leading invasive cancer among women worldwide. BCa-related mortality is usually caused by distant metastases rather than primary tumors (1, 2). The spread of cancer cells from primary tumors to distant organs, termed metastasis, is a multistep process in which cancer cells must (i) invade through the extracellular matrix (ECM), (ii) disseminate into the bloodstream, (iii) survive in the circulation, and (iv) extravasate and successfully colonize distant sites (3). Conventional therapeutic strategies have limited success in preventing and treating metastatic cancer, and BCa metastases can recur many years after removal of the primary tumor. This phenomenon could be due to the complex nature of metastasis itself, and, more realistically, the limitation of current treatments that are effective against primary BCa, i.e., surgical removal and localized radiotherapy, but do little to prevent metastatic recurrence. Even chemotherapy is not very effective against metastatic tumors (4). Unfortunately, the pharmaceutical industry has been reluctant to conduct metastasis prevention trials on patients with early stage cancer using survival and reduction of metastatic load as end points, because such studies are lengthy and require a large number of patients with otherwise relatively good survival prospects (4). Consequently, the development of agents that prevent metastasis from occurring and trigger regression of established metastatic lesions is an urgent unmet need.It was reported that expression of the ubiquitin conjugating enzyme (E2) Ubc13 is up-regulated in metastatic BCa (5). Ubc13, which heterodimerizes with Uev1a, catalyzes formation of lysine 63 (K63)-linked polyubiquitin chains, which control protein-protein interactions involved in DNA damage repair and protein kinase activation (6, 7). In certain immune cells, Ubc13 is required for IκB kinase (IKK)-nuclear factor κB (NF-κB) activation, but a more ubiquitous role for Ubc13 was observed in the activation of MAPK signaling (8-11). We found that Ubc13 is required for activation of mitogen-a...