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Objective Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease. Design Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of KrasG12D-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition. Results We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours. Conclusions KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future.

BackgroundProstate cancer is highly prevalent worldwide. Androgen deprivation therapy (ADT) remains the treatment of choice for incurable prostate cancer, but majority of patients develop disease recurrence following ADT. There is therefore an urgent need for early detection of treatment resistance.MethodsIsogenic androgen-responsive (CWR22Res) and castration-resistant (22Rv1) human prostate cancer cells were implanted into the anterior lobes of the prostate in CD-1 Nu mice to generate prostate orthografts. Castrated mice bearing CWR22Res and 22Rv1 orthografts mimic clinical prostate cancer following acute and chronic ADT, respectively. 18F-Fluciclovine (1-amino-3-fluorocyclobutane-1-carboxylic acid) with a radiochemical purity of > 99% was produced on a FASTlab synthesiser. Ki67 staining in endpoint orthografts was studied. Western blot, quantitative RT-PCR and next-generation sequencing transcriptomic analyses were performed to assess the expression levels of amino acid transporters (including LAT1 and ASCT2, which have been implicated for Fluciclovine uptake). Longitudinal metabolic imaging with 18F-Fluciclovine-based positron emission tomography (PET) was performed to study tumour response following acute and chronic ADT. ResultsBoth immunohistochemistry analysis of endpoint prostate tumours and longitudinal 18F-Fluciclovine imaging revealed tumour heterogeneity, particularly following ADT, with in vivo 18F-Fluciclovine uptake correlating to viable cancer cells in both androgen-proficient and castrated environment. Highlighting tumour subpopulation following ADT, both SUVpeak and coefficient of variation (CoV) values of 18F-Fluciclovine uptake are consistent with tumour heterogeneity revealed by immunohistochemistry. We studied the expression of amino acid transporters (AATs) for 18F-Fluciclovine, namely LAT1 (SLC7A5 and SLC3A2) and ASCT2 (SLC1A5). SLC7A5 and SLC3A2 were expressed at relatively high levels in 22Rv1 castration-resistant orthografts following chronic ADT (modelling clinical castration-resistant disease), while SLC1A5 was preferentially expression in CWR22Res tumours following acute ADT. Additional AATs such as SLC43A2 (LAT4) were shown to be upregulated following chronic ADT by transcriptomic analysis; their role in Fluciclovine uptake warrants investigation.ConclusionWe studied in vivo 18F-Fluciclovine uptake in human prostate cancer orthograft models following acute and chronic ADT. 18F-Fluciclovine uptakes highlight tumour heterogeneity that may explain castration resistance and can be exploited as a clinical biomarker.

It is now well established that tumours undergo changes in cellular metabolism 1 . As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake 2 , we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose 3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types. Mannose reduces the growth of tumour cells by impairing the metabolism of glucose, and enhances cell death when used in combination with conventional chemotherapy.

In a mouse model of pancreatic tumours driven by Kras mutations, the outcome of suppressing autophagy is shown to depend on the status of p53: if p53 is intact, deletion of key autophagy genes blocks the progression of pre-cancerous lesions to aggressive carcinomas; however, in the absence of p53, loss of autophagy accelerates tumorigenesis, accompanied by deregulation of cancer cell metabolism. Role of autophagy depends on p53 Whether autophagy — the degradation of damaged or superfluous cellular material — promotes or suppresses tumorigenesis has long been a matter of controversy. Recent evidence suggests that both may be true depending on the context. Kevin Ryan et al . now show in a mouse model of pancreatic tumours driven by Kras mutations that the outcome of suppressing autophagy depends on the status of p53. If p53 is intact, deletion of key autophagy genes blocks the progression of low-grade tumours to aggressive carcinomas. But in the absence of p53, loss of autophagy accelerates tumorigenesis, accompanied by deregulation of cancer cell metabolism. This work has important implications for the idea of targeting autophagy in cancer. Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation 1 . Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease 2 , 3 , 4 . The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . Here we show, in a humanized genetically-modified mouse model of pancreatic ductal adenocarcinoma (PDAC), that autophagy’s role in tumour development is intrinsically connected to the status of the tumour suppressor p53. Mice with pancreases containing an activated oncogenic allele of Kras (also called Ki-Ras)—the most common mutational event in PDAC 13 —develop a small number of pre-cancerous lesions that stochastically develop into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 or Atg7 accumulate low-grade, pre-malignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC is blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocks tumour progression, but actually accelerates tumour onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumour growth. These findings provide considerable insight into the role of autophagy in cancer and have important implications for autophagy inhibition in cancer therapy. In this regard, we also show that treatment of mice with the autophagy inhibitor hydroxychloroquine, which is currently being used in several clinical trials 14 , significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53.

Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation (1). Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease (2-4). The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles (3,5-12). Here we show, in a humanized geneticallymodified mouse model of pancreatic ductal adenocarcinoma (PDAC), that autophagy's role in tumour development is intrinsically connected to the status of the tumour suppressor p53. Mice with pancreases containing an activated oncogenic allele of Kras (also called Ki-Ras)--the most common mutational event in PDAC (13) --develop a small number of pre-cancerous lesions that stochastically develop into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 or Atg7 accumulate low-grade, pre-malignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC is blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocks tumour progression, but actually accelerates tumour onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumour growth. These findings provide considerable insight into the role of autophagy in cancer and have important implications for autophagy inhibition in cancer therapy. In this regard, we also show that treatment of mice with the autophagy inhibitor hydroxychloroquine, which is currently being used in several clinical trials (14), significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53.

This article seeks to present the way in which the Afrofuturism as a literary genre can be used to reflect on the potential of the African future. In the novel Rouge impératrice, published in 2019, Cameroonian author Léonora Miano introduces a vision of the future united state of Katiopa which enables her to reconsider some present problems and offered socio-political solutions. The image of the possible future of the African states constitutes a clever and innovative analysis of the current political and cultural issues of the African continent, and its possibilities for a stable and peaceful progress. At the same time, Miano tries to stay clear of the category of Black utopia.

“The Africa That’s Coming”: A Non-utopian Vision of the Future in Léonora Miano’s Rouge impératrice This article seeks to present the way in which the Afrofuturism as a literary genre can be used to reflect on the potential of the African future. In the novel Rouge impératrice, published in 2019, Cameroonian author Léonora Miano introduces a vision of the future united state of Katiopa which enables her to reconsider some present problems and offered socio-political solutions. The image of the possible future of the African states constitutes a clever and innovative analysis of the current political and cultural issues of the African continent, and its possibilities for a stable and peaceful progress. At the same time, Miano tries to stay clear of the category of Black utopia.

This article seeks to present the way in which the Afrofuturism as a literary genre can be used to reflect on the potential of the African future. In the novel Rouge impératrice, published in 2019, Cameroonian author Léonora Miano introduces a vision of the future united state of Katiopa which enables her to reconsider some present problems and offered socio-political solutions. The image of the possible future of the African states constitutes a clever and innovative analysis of the current political and cultural issues of the African continent, and its possibilities for a stable and peaceful progress. At the same time, Miano tries to stay clear of the category of Black utopia.