• Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial

  Parker, CC; James, ND; Brawley, CD; Clarke, Noel W; Hoyle, Alex, P; Ali, Adnan; Ritchie, AWS; Attard, G; Chowdhury, S; Cross, W; Dearnaley, DP; Gillessen, Silke; Gilson, C; Jones, RJ; Langley, RE; Malik, ZI; Mason, MD; Matheson, D; Millman, R; Russell, JM; Thalmann, GN; Amos, CL; Alonzi, R; Bahl, A; Birtle, A; Din, O; Douis, H; Eswar, C; Gale, J; Gannon, MR; Jonnada, S; Khaksar, S; Lester, JF; O'Sullivan, JM; Parikh, OA; Pedley, ID; Pudney, DM; Sheehan, DJ; Srihari, NN; Tran, Anna, T; Parmar, MKB; Sydes, MR; Academic Urology Unit, Royal Marsden Hospital, London, UK (2018)
• Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion.

  Rhost, S; Hughes, E; Harrison, Hannah; Rafnsdottir, S; Jacobsson, H; Gregersson, P; Magnusson, Y; Fitzpatrick, P; Andersson, D; Berger, K; Stahlberg, A; Landberg, Goran; Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden (2018)

  BACKGROUND: Cancer progression is influenced by genetic aberrations in the cancer cell population as well as by other factors including the microenvironment present within a tumour. Direct interactions between various cell types as well as cellular signalling via secreted cytokines can drive key tumourigenic properties associated with disease progression and treatment resistance. Also, cancer stem cell functions are influenced by the microenvironment. This challenging subset of cells has been linked to malignant properties. Within a screen, using in vivo like growth conditions, we identified progranulin as a highly secreted cytokine affecting cancer stem cells in breast cancer. This cytokine is known to play a role in numerous biological and tumour-related processes including therapy resistance in a range of cancer types. METHODS: Different in vitro and in vivo relevant conditions were used to validate breast cancer stem cell expansion mediated by progranulin and its receptor sortilin. Small interfering ribonucleic acid (siRNA) and pharmacological inhibition of sortilin were used to elucidate the role of sortilin as a functional receptor during progranulin-induced breast cancer stem cell propagation, both in vitro and in vivo, using breast cancer xenograft models. In addition, single-cell gene expression profiling as well as a Sox2 reporter breast cancer cell line were used to validate the role of dedifferentiation mediated by progranulin. RESULTS: In various in vivo-like screening assays, progranulin was identified as a potent cancer stem cell activator, highly secreted in ER?-negative breast cancer as well as in ER?-positive breast cancer under hypoxic adaptation. Progranulin exposure caused dedifferentiation as well as increased proliferation of the cancer stem cell pool, a process that was shown to be dependent on its receptor sortilin. Subcutaneous injections of progranulin or its active domain (GRN A) induced lung metastases in breast cancer xenograft models, supporting a major role for progranulin in cancer progression. Importantly, an orally bioavailable small molecule (AF38469) targeting sortilin, blocked GRN A-induced lung metastases and prevented cancer cell infiltration of the skin. CONCLUSION: The collective results suggest that sortilin targeting represents a potential novel breast cancer therapy approach inhibiting tumour progression driven by secretion and microenvironmental influences. KEYWORDS: Breast cancer; Cancer stem cells; Dedifferentiation; Differentiation; Hypoxia; Metastasis; Secretion
• The p38 alpha stress kinase suppresses aneuploidy tolerance by inhibiting Hif-1 alpha.

  Simoes-Sousa, Susana; Littler, Samantha; Thompson, Sarah L; Minshall, Paul; Whalley, Helen J; Bakker, B; Belkot, Klaudyna; Moralli, D; Bronder, Daniel; Tighe, Anthony; Spierings, DCJ; Bah, Nourdine; Graham, Joshua; Nelson, Louisa; Green, CM; Foijer, F; Townsend, Paul A; Taylor, Stephen S; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4QL (2018)

  Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. We also show that p38 deficiency upregulates the hypoxia-inducible transcription factor Hif-1? and that inhibiting Hif-1? restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1? to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia.
• Intercomparison exercises: why is it important to calibrate radionuclide calibrators for different radionuclides.

  Ferreira, KM; Fenwick, AJ; Robinson, Andrew P; Denis-Bacelar, AM; Wevrett, J; Keightley, JD; National Physical Laboratory,Teddington (2018)
• A novel method for accurate activity measurements of emerging Th-227-labelled conjugates.

  Fenwick, AJ; Keightley, JD; Denis-Bacelar, AM; Ferreira, KM; Wevrett, JL; Robinson, Andrew P; National Physical Laboratory,Teddington (2018)

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