Tubular epithelia are a basic building block of organs and a common site of cancer occurrence 1-4. During tumourigenesis, transformed cells overproliferate and epithelial architecture is disrupted. The biophysical parameters underlying the adoption of abnormal tumour tissue shapes are, however, not known. Here we show that the morphology of epithelial tumours is determined by the interplay of cytoskeletal changes in transformed cells and the existing tubular geometry. To analyse the morphological changes of tissue architecture during cancer initiation, we developed a three-dimensional (3D) whole organ imaging technique allowing tissue analysis at single cell resolution. Oncogenic transformation of pancreatic ducts led to two types of neoplastic growth: exophytic lesions expanding outwards from the duct, and endophytic lesions growing inwards to the ductal lumen. Myosin activity was higher apically than basally in wildtype cells but upon transformation, this gradient was lost in both lesion types. 3D vertex model simulations and a continuum theory of epithelial mechanics, incorporating the cytoskeletal changes observed in *

Pancreatic ductal adenocarcinoma (PDAC) shows great cellular heterogeneity, with pronounced epithelial and mesenchymal cancer cell populations. However, the cellular hierarchy underlying PDAC cell diversity is unknown. Here we identify the tetraspanin CD9 as a marker of PDAC tumour-initiating cells. CD9 high cells had increased organoid formation capability, and generated tumour grafts in vivo at limiting dilutions. Tumours initiated from CD9 high cells recapitulated the cellular heterogeneity of primary PDAC, whereas CD9 low cells only produced duct-like epithelial progeny. CD9 knockdown decreased the growth of PDAC organoids, and heterozygous CD9 deletion in Pdx1-Cre; LSL-KRas G12D ; p53 F/F mice prolonged overall survival. Mechanistically, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

We have recently recapitulated metastasis of human PTEN/TP53-mutant PC in mouse using the RapidCaP system. Surprisingly, we found that this metastasis is driven by Myc-, and not Akt-activation. Here, we show that cell-cell communication by Il6 drives the Akt-Myc switch through activation of the Akt-suppressing phosphatase Phlpp2, when Pten and p53 are lost together, but not separately. Il6 then communicates a downstream program of Stat3-mediated Myc-activation, which drives cell proliferation. Similarly in tissues, peak proliferation in Pten/Trp53 mutant primary and metastatic PC does not correlate with activated Akt, but with Stat3/Myc activation instead. Mechanistically, Myc strongly activates the Akt phosphatase Phlpp2 in primary cells and PC metastasis. We show genetically that Phlpp2 is essential for dictating proliferation of Myc-mediated Akt-suppression. Collectively, our data reveal competition between two proto-oncogenes: Myc and Akt, which ensnarls the Phlpp2 gene to facilitate Myc-driven PC metastasis after loss of Pten and Trp53.

Reduced PTEN protein is linked to tumorigenesis. Here, Chen et al. show that the nuclear transport receptor Importin-11 separates PTEN from degradation machinery. IPO11 mutant mice exhibit PTEN degradation, lung adenocarcinoma, and prostate neoplasia. In human prostatectomy patients, IPO11 status predicts disease recurrence and metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is driven by metabolic changes in pancreatic cells caused by oncogenic mutations and dysregulation of p53. PDAC cell lines and PDAC-derived xenografts grow as a result of altered metabolic pathways, changes in stroma, and autophagy. Selective targeting and inhibition of one of these may open avenues for the development of new therapeutic strategies. In this study, we performed a genome-wide siRNA screen in a PDAC cell line using endogenous autophagy as a readout and identified several regulators of autophagy that were required for autophagy-dependent PDAC cell survival. Validation of two promising candidates, MPP7 (MAGUK p55 subfamily member 7, a scaffolding protein involved in cell-cell contacts) and MDH1 (cytosolic Malate dehydrogenase 1), revealed their role in early stages of autophagy during autophagosome formation. MPP7 was involved in activation of YAP1 (a transcriptional coactivator in the Hippo pathway), which in turn promoted autophagy, whereas MDH1 was required for maintenance of the levels of the essential autophagy initiator serine-threonine kinase ULK1, and increased in activity upon induction of autophagy. Our results provide a possible explanation for how autophagy is regulated by MPP7 and MDH1, which adds to our understanding of autophagy regulation in PDAC.