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Open AccessEditorial

Basic and Translational Models of Cooperative Oncogenesis

by Helena E. Richardson, Julia B. Cordero and Daniela Grifoni

Int. J. Mol. Sci. 2020, 21(16), 5919; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165919 - 18 Aug 2020

Cited by 4 | Viewed by 2237

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(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis)

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21 pages, 10591 KiB

Open AccessArticle

Rounding up the Usual Suspects: Assessing Yorkie, AP-1, and Stat Coactivation in Tumorigenesis

by Fisun Hamaratoglu and Mardelle Atkins

Int. J. Mol. Sci. 2020, 21(13), 4580; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134580 - 27 Jun 2020

Cited by 9 | Viewed by 3186

Abstract

Can hyperactivation of a few key signaling effectors be the underlying reason for the majority of epithelial cancers despite different driver mutations? Here, to address this question, we use the Drosophila model, which allows analysis of gene expression from tumors with known initiating [...] Read more.

Can hyperactivation of a few key signaling effectors be the underlying reason for the majority of epithelial cancers despite different driver mutations? Here, to address this question, we use the Drosophila model, which allows analysis of gene expression from tumors with known initiating mutations. Furthermore, its simplified signaling pathways have numerous well characterized targets we can use as pathway readouts. In Drosophila tumor models, changes in the activities of three pathways, Jun N-terminal Kinase (JNK), Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), and Hippo, mediated by AP-1 factors, Stat92E, and Yorkie, are reported frequently. We hypothesized this may indicate that these three pathways are commonly deregulated in tumors. To assess this, we mined the available transcriptomic data and evaluated the activity levels of eight pathways in various tumor models. Indeed, at least two out of our three suspects contribute to tumor development in all Drosophila cancer models assessed, despite different initiating mutations or tissues of origin. Surprisingly, we found that Notch signaling is also globally activated in all models examined. We propose that these four pathways, JNK, JAK/STAT, Hippo, and Notch, are paid special attention and assayed for systematically in existing and newly developed models. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis)

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16 pages, 12029 KiB

Open AccessArticle

The Splicing Factor SF2 Is Critical for Hyperproliferation and Survival in a TORC1-Dependent Model of Early Tumorigenesis in Drosophila

by Malgorzata Maria Parniewska and Hugo Stocker

Int. J. Mol. Sci. 2020, 21(12), 4465; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124465 - 24 Jun 2020

Cited by 3 | Viewed by 2720

Abstract

The Target of Rapamycin complex 1 (TORC1) is an evolutionarily conserved kinase complex coordinating cellular growth with nutritional conditions and growth factor signaling, and its activity is elevated in many cancer types. The use of TORC1 inhibitors as anticancer drugs is, however, limited [...] Read more.

The Target of Rapamycin complex 1 (TORC1) is an evolutionarily conserved kinase complex coordinating cellular growth with nutritional conditions and growth factor signaling, and its activity is elevated in many cancer types. The use of TORC1 inhibitors as anticancer drugs is, however, limited by unwanted side-effects and development of resistance. We therefore attempted to identify limiting modulators or downstream effectors of TORC1 that could serve as therapeutic targets. Drosophila epithelial tissues that lack the tumor suppressor Pten hyperproliferate upon nutrient restriction in a TORC1-dependent manner. We probed candidates of the TORC1 signaling network for factors limiting the overgrowth of Pten mutant tissues. The serine/arginine-rich splicing factor 2 (SF2) was identified as the most limiting factor: SF2 knockdown drives Pten mutant cells into apoptosis, while not affecting control tissue. SF2 acts downstream of or in parallel to TORC1 but is not required for the activation of the TORC1 target S6K. Transcriptomics analysis revealed transcripts with alternatively used exons regulated by SF2 in the tumor context, including p53. SF2 may therefore represent a highly specific therapeutic target for tumors with hyperactive TORC1 signaling. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis)

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16 pages, 3987 KiB

Open AccessArticle

The Microarchitecture of Pancreatic Cancer as Measured by Diffusion-Weighted Magnetic Resonance Imaging Is Altered by T Cells with a Tumor Promoting Th17 Phenotype

by Philipp Mayer, Alica Linnebacher, Hannah Glennemeier-Marke, Nicole Marnet, Frank Bergmann, Thilo Hackert, Miriam Klauss, Tanja Poth and Matthias M. Gaida

Int. J. Mol. Sci. 2020, 21(1), 346; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010346 - 05 Jan 2020

Cited by 11 | Viewed by 3583

Abstract

Diffusion-weighted magnetic resonance imaging (DW-MRI) is a diagnostic tool that is increasingly used for the detection and characterization of focal masses in the abdomen, among these, pancreatic ductal adenocarcinoma (PDAC). DW-MRI reflects the microarchitecture of the tissue, and changes in diffusion, which are [...] Read more.

Diffusion-weighted magnetic resonance imaging (DW-MRI) is a diagnostic tool that is increasingly used for the detection and characterization of focal masses in the abdomen, among these, pancreatic ductal adenocarcinoma (PDAC). DW-MRI reflects the microarchitecture of the tissue, and changes in diffusion, which are reflected by changes in the apparent diffusion coefficient (ADC), are mainly attributed to variations in cellular density, glandular formation, and fibrosis. When analyzing the T cell infiltrates, we found an association of a tumor-promoting subpopulation, characterized by the expression of interleukin (IL) 21 and IL26, with high ADC values. Moreover, the presence of IL21⁺ and IL26⁺ positive T cells was associated with poor prognosis. Pancreatic cancers—but not healthy pancreatic tissue—expressed receptors for IL21 and IL26, a finding that could be confirmed in pancreatic cell lines. The functionality of these receptors was demonstrated in pancreatic tumor cell lines, which showed phosphorylation of ERK1/2 and STAT3 pathways in response to the respective recombinant interleukins. Moreover, in vitro data showed an increased colony formation of tumor cells. In summary, our data showed an association of IL21⁺ and IL26⁺ immune cell infiltration, increased ADC, and aggressive tumor disease, most likely due to the activation of the key cancer signaling pathways ERK1/2 and STAT3 and formation of tumor colonies. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis)

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22 pages, 6822 KiB

Open AccessArticle

Genetic Programs Driving Oncogenic Transformation: Lessons from In Vitro Models

by Eros Di Giorgio, Harikrishnareddy Paluvai, Raffaella Picco and Claudio Brancolini

Int. J. Mol. Sci. 2019, 20(24), 6283; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246283 - 12 Dec 2019

Cited by 6 | Viewed by 2918

Abstract

Cancer complexity relies on the intracellular pleiotropy of oncogenes/tumor suppressors and in the strong interplay between tumors and micro- and macro-environments. Here we followed a reductionist approach, by analyzing the transcriptional adaptations induced by three oncogenes (RAS, MYC, and HDAC4 [...] Read more.

Cancer complexity relies on the intracellular pleiotropy of oncogenes/tumor suppressors and in the strong interplay between tumors and micro- and macro-environments. Here we followed a reductionist approach, by analyzing the transcriptional adaptations induced by three oncogenes (RAS, MYC, and HDAC4) in an isogenic transformation process. Common pathways, in place of common genes became dysregulated. From our analysis it emerges that, during the process of transformation, tumor cells cultured in vitro prime some signaling pathways suitable for coping with the blood supply restriction, metabolic adaptations, infiltration of immune cells, and for acquiring the morphological plasticity needed during the metastatic phase. Finally, we identified two signatures of genes commonly regulated by the three oncogenes that successfully predict the outcome of patients affected by different cancer types. These results emphasize that, in spite of the heterogeneous mutational burden among different cancers and even within the same tumor, some common hubs do exist. Their location, at the intersection of the various signaling pathways, makes a therapeutic approach exploitable. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis)

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14 pages, 1134 KiB

Open AccessReview

Strategies for Functional Interrogation of Big Cancer Data Using Drosophila Cancer Models

by Erdem Bangi

Int. J. Mol. Sci. 2020, 21(11), 3754; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113754 - 26 May 2020

Cited by 4 | Viewed by 2416

Abstract

Rapid development of high throughput genome analysis technologies accompanied by significant reduction in costs has led to the accumulation of an incredible amount of data during the last decade. The emergence of big data has had a particularly significant impact in biomedical research [...] Read more.

Rapid development of high throughput genome analysis technologies accompanied by significant reduction in costs has led to the accumulation of an incredible amount of data during the last decade. The emergence of big data has had a particularly significant impact in biomedical research by providing unprecedented, systems-level access to many disease states including cancer, and has created promising opportunities as well as new challenges. Arguably, the most significant challenge cancer research currently faces is finding effective ways to use big data to improve our understanding of molecular mechanisms underlying tumorigenesis and developing effective new therapies. Functional exploration of these datasets and testing predictions from computational approaches using experimental models to interrogate their biological relevance is a key step towards achieving this goal. Given the daunting scale and complexity of the big data available, experimental systems like Drosophila that allow large-scale functional studies and complex genetic manipulations in a rapid, cost-effective manner will be of particular importance for this purpose. Findings from these large-scale exploratory functional studies can then be used to formulate more specific hypotheses to be explored in mammalian models. Here, I will discuss several strategies for functional exploration of big cancer data using Drosophila cancer models. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis)

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12 pages, 1830 KiB

Open AccessReview

The Case of the Scribble Polarity Module in Asymmetric Neuroblast Division in Development and Tumorigenesis

by Ana Carmena

Int. J. Mol. Sci. 2020, 21(8), 2865; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082865 - 20 Apr 2020

Cited by 2 | Viewed by 2832

Abstract

The Scribble polarity module is composed by Scribble (Scrib), Discs large 1 (Dlg1) and Lethal (2) giant larvae (L(2)gl), a group of highly conserved neoplastic tumor suppressor genes (TSGs) from flies to humans. Even though the Scribble module has been profusely studied in [...] Read more.

The Scribble polarity module is composed by Scribble (Scrib), Discs large 1 (Dlg1) and Lethal (2) giant larvae (L(2)gl), a group of highly conserved neoplastic tumor suppressor genes (TSGs) from flies to humans. Even though the Scribble module has been profusely studied in epithelial cell polarity, the number of tissues and processes in which it is involved is increasingly growing. Here we discuss the role of the Scribble module in the asymmetric division of Drosophila neuroblasts (NBs), as well as the underlying mechanisms by which those TSGs act in this process. Finally, we also describe what we know about the consequences of mutating these genes in impairing the process of asymmetric NB division and promoting tumor-like overgrowth. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis)

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15 pages, 1397 KiB

Open AccessReview

Oncogenic Roles of GOLPH3 in the Physiopathology of Cancer

by Stefano Sechi, Anna Frappaolo, Angela Karimpour-Ghahnavieh, Roberto Piergentili and Maria Grazia Giansanti

Int. J. Mol. Sci. 2020, 21(3), 933; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030933 - 31 Jan 2020

Cited by 50 | Viewed by 5383

Abstract

Golgi phosphoprotein 3 (GOLPH3), a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, is required for Golgi ribbon structure maintenance, vesicle trafficking and Golgi glycosylation. GOLPH3 has been validated as an oncoprotein through combining integrative genomics with clinopathological and functional analyses. It is frequently [...] Read more.

Golgi phosphoprotein 3 (GOLPH3), a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, is required for Golgi ribbon structure maintenance, vesicle trafficking and Golgi glycosylation. GOLPH3 has been validated as an oncoprotein through combining integrative genomics with clinopathological and functional analyses. It is frequently amplified in several solid tumor types including melanoma, lung cancer, breast cancer, glioma, and colorectal cancer. Overexpression of GOLPH3 correlates with poor prognosis in multiple tumor types including 52% of breast cancers and 41% to 53% of glioblastoma. Roles of GOLPH3 in tumorigenesis may correlate with several cellular activities including: (i) regulating Golgi-to-plasma membrane trafficking and contributing to malignant secretory phenotypes; (ii) controlling the internalization and recycling of key signaling molecules or increasing the glycosylation of cancer relevant glycoproteins; and (iii) influencing the DNA damage response and maintenance of genomic stability. Here we summarize current knowledge on the oncogenic pathways involving GOLPH3 in human cancer, GOLPH3 influence on tumor metabolism and surrounding stroma, and its possible role in tumor metastasis formation. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis)

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15 pages, 1216 KiB

Open AccessReview

Cytonemes, Their Formation, Regulation, and Roles in Signaling and Communication in Tumorigenesis

by Sergio Casas-Tintó and Marta Portela

Int. J. Mol. Sci. 2019, 20(22), 5641; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225641 - 11 Nov 2019

Cited by 19 | Viewed by 4375

Abstract

Increasing evidence during the past two decades shows that cells interconnect and communicate through cytonemes. These cytoskeleton-driven extensions of specialized membrane territories are involved in cell–cell signaling in development, patterning, and differentiation, but also in the maintenance of adult tissue homeostasis, tissue regeneration, [...] Read more.

Increasing evidence during the past two decades shows that cells interconnect and communicate through cytonemes. These cytoskeleton-driven extensions of specialized membrane territories are involved in cell–cell signaling in development, patterning, and differentiation, but also in the maintenance of adult tissue homeostasis, tissue regeneration, and cancer. Brain tumor cells in glioblastoma extend ultralong membrane protrusions (named tumor microtubes, TMs), which contribute to invasion, proliferation, radioresistance, and tumor progression. Here we review the mechanisms underlying cytoneme formation, regulation, and their roles in cell signaling and communication in epithelial cells and other cell types. Furthermore, we discuss the recent discovery of glial cytonemes in the Drosophila glial cells that alter Wingless (Wg)/Frizzled (Fz) signaling between glia and neurons. Research on cytoneme formation, maintenance, and cell signaling mechanisms will help to better understand not only physiological developmental processes and tissue homeostasis but also cancer progression. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis)

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15 pages, 1439 KiB

Open AccessReview

Co-Operation between Aneuploidy and Metabolic Changes in Driving Tumorigenesis

by David L. Newman and Stephen L. Gregory

Int. J. Mol. Sci. 2019, 20(18), 4611; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184611 - 18 Sep 2019

Cited by 12 | Viewed by 3880

Abstract

Alterations from the normal set of chromosomes are extremely common as cells progress toward tumourigenesis. Similarly, we expect to see disruption of normal cellular metabolism, particularly in the use of glucose. In this review, we discuss the connections between these two processes: how [...] Read more.

Alterations from the normal set of chromosomes are extremely common as cells progress toward tumourigenesis. Similarly, we expect to see disruption of normal cellular metabolism, particularly in the use of glucose. In this review, we discuss the connections between these two processes: how chromosomal aberrations lead to metabolic disruption, and vice versa. Both processes typically result in the production of elevated levels of reactive oxygen species, so we particularly focus on their role in mediating oncogenic changes. Full article

(This article belongs to the Special Issue Basic and Translational Models of Cooperative Oncogenesis)

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