bims-pideca 2021-01-10 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2021–01–10
nine papers selected by
Ralitsa Radostinova Madsen, University College London

Characterization and Childhood Tumor Risk Assessment of Genetic and Epigenetic Syndromes Associated With Lateralized Overgrowth.
Insulin signaling in health and disease.
Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders.
MTORC1-Regulated Metabolism Controlled by TSC2 Limits Cardiac Reperfusion Injury.
A Review of PI3K Inhibitors in B-Cell Malignancies.
An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence.
Computational Stem Cell Biology: Open Questions and Guiding Principles.
Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium.
β-Trcp and CK1δ-mediated degradation of LZTS2 activates PI3K/AKT signaling to drive tumorigenesis and metastasis in hepatocellular carcinoma.

Front Pediatr. 2020 ;8 613260

Characterization and Childhood Tumor Risk Assessment of Genetic and Epigenetic Syndromes Associated With Lateralized Overgrowth.

Jessica R Griff, Kelly A Duffy, Jennifer M Kalish.

  Lateralized overgrowth (LO), or segmental overgrowth, is defined as an increase in growth of tissue (bone, muscle, connective tissue, vasculature, etc.) in any region of the body. Some overgrowth syndromes, characterized by both generalized and lateralized overgrowth, have been associated with an increased risk of tumor development. This may be due to the underlying genetic and epigenetic defects that lead to disrupted cell growth and proliferation pathways resulting in the overgrowth and tumor phenotypes. This chapter focuses on the four most common syndromes characterized by LO: Beckwith-Wiedemann spectrum (BWSp), PIK3CA-related overgrowth spectrum (PROS), Proteus syndrome (PS), and PTEN hamartoma tumor syndrome (PHTS). These syndromes demonstrate variable risks for tumor development in patients affected by LO, and we provide a comprehensive literature review of all common tumors reported in patients diagnosed with an LO-related disorder. This review summarizes the current data on tumor risk among these disorders and their associated tumor screening guidelines. Furthermore, this chapter highlights the importance of an accurate diagnosis when a patient presents with LO as similar phenotypes are associated with different tumor risks, thereby altering preventative screening protocols.

Keywords:  Beckwith-Wiedemann spectrum; Beckwith-Wiedemann syndrome (BWS); PIK3CA-related overgrowth spectrum (PROS); PTEN hamartoma tumor syndrome; Proteus syndrome (PS); hemihyperplasia; hemihypertrophy; lateralized overgrowth

DOI:  https://doi.org/10.3389/fped.2020.613260
J Clin Invest. 2021 Jan 04. pii: 142241. [Epub ahead of print]131(1):

Insulin signaling in health and disease.

Alan R Saltiel.

The molecular mechanisms of cellular insulin action have been the focus of much investigation since the discovery of the hormone 100 years ago. Insulin action is impaired in metabolic syndrome, a condition known as insulin resistance. The actions of the hormone are initiated by binding to its receptor on the surface of target cells. The receptor is an α2β2 heterodimer that binds to insulin with high affinity, resulting in the activation of its tyrosine kinase activity. Once activated, the receptor can phosphorylate a number of intracellular substrates that initiate discrete signaling pathways. The tyrosine phosphorylation of some substrates activates phosphatidylinositol-3-kinase (PI3K), which produces polyphosphoinositides that interact with protein kinases, leading to activation of the kinase Akt. Phosphorylation of Shc leads to activation of the Ras/MAP kinase pathway. Phosphorylation of SH2B2 and of Cbl initiates activation of G proteins such as TC10. Activation of Akt and other protein kinases produces phosphorylation of a variety of substrates, including transcription factors, GTPase-activating proteins, and other kinases that control key metabolic events. Among the cellular processes controlled by insulin are vesicle trafficking, activities of metabolic enzymes, transcriptional factors, and degradation of insulin itself. Together these complex processes are coordinated to ensure glucose homeostasis.

DOI: https://doi.org/10.1172/JCI142241
Elife. 2020 12 16. pii: e56630. [Epub ahead of print]9

Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders.

Helen Wong, Josien Levenga, Lauren LaPlante, Bailey Keller, Andrew Cooper-Sansone, Curtis Borski, Ryan Milstead, Marissa Ehringer, Charles Hoeffer.

  AKT is implicated in neurological disorders. AKT has three isoforms, AKT1/AKT2/AKT3, with brain cell type-specific expression that may differentially influence behavior. Therefore, we examined single Akt isoform, conditional brain-specific Akt1, and double Akt1/3 mutant mice in behaviors relevant to neuropsychiatric disorders. Because sex is a determinant of these disorders but poorly understood, sex was an experimental variable in our design. Our studies revealed AKT isoform- and sex-specific effects on anxiety, spatial and contextual memory, and fear extinction. In Akt1 mutant males, viral-mediated AKT1 restoration in the prefrontal cortex rescued extinction phenotypes. We identified a novel role for AKT2 and overlapping roles for AKT1 and AKT3 in long-term memory. Finally, we found that sex-specific behavior effects were not mediated by AKT expression or activation differences between sexes. These results highlight sex as a biological variable and isoform- or cell type-specific AKT signaling as potential targets for improving treatment of neuropsychiatric disorders.

Keywords:  associative memory; extinction; hippocampus; isoform; mouse; neuroscience; prefrontal cortex; spatial learning

DOI:  https://doi.org/10.7554/eLife.56630
Circ Res. 2021 Jan 06.

MTORC1-Regulated Metabolism Controlled by TSC2 Limits Cardiac Reperfusion Injury.

Christian U Oeing, Seungho Jun, Sumita Mishra, Brittany Dunkerly-Eyring, Anna Chen, Maria I Grajeda, Usman Tahir, Robert E Gerszten, Nazareno Paolocci, Mark J Ranek, David A Kass.

  Rationale: The mechanistic target of rapamycin complex-1 (mTORC1) controls metabolism and protein homeostasis, and is activated following ischemic reperfusion (IR) injury and by ischemic preconditioning (IPC). However, studies vary as to whether this activation is beneficial or detrimental, and its influence on metabolism after IR is little studied. A limitation of prior investigations is their use of broad gain/loss of mTORC1 function, mostly applied prior to ischemic stress. This can be circumvented by regulating one serine (S1365) on tuberous sclerosis complex (TSC2) to achieve bi-directional mTORC1 modulation but only with TCS2-regulated co-stimulation. Objective: We tested the hypothesis that reduced TSC2 S1365 phosphorylation protects the myocardium against IR and IPC by amplifying mTORC1 activity to favor glycolytic metabolism. Methods and Results: Mice with either S1365A (TSC2SA; phospho-null) or S1365E (TSC2SE; phosphomimetic) knock-in mutations were studied ex vivo and in vivo. In response to IR, hearts from TSC2SA mice had amplified mTORC1 activation and improved heart function compared to WT and TSC2SE hearts. The magnitude of protection matched IPC. IPC requited less S1365 phosphorylation, as TSC2SE hearts gained no benefit and failed to activate mTORC1 with IPC. IR metabolism was altered in TSC2SA, with increased mitochondrial oxygen consumption rate and glycolytic capacity (stressed/maximal extracellular acidification) after myocyte hypoxia-reperfusion. In whole heart, lactate increased and long-chain acyl-carnitine levels declined during ischemia. The relative IR protection in TSC2SA was lost by lowering glucose in the perfusate by 36%. Adding fatty acid (palmitate) compensated for reduced glucose in WT and TSC2SE but not TSC2SA which had the worst post-IR function under these conditions. Conclusions: TSC2-S1365 phosphorylation status regulates myocardial substrate utilization, and its decline activates mTORC1 biasing metabolism away from fatty acid oxidation to glycolysis to confer protection against IR. This pathway is also engaged and reduced TSC2 S1365 phosphorylation required for effective IPC.

Keywords:  mechanistic target of rapamycin; tuberous sclerosis complex

DOI:  https://doi.org/10.1161/CIRCRESAHA.120.317710
J Adv Pract Oncol. 2019 Sep-Oct;10(7):10(7): 715-725

A Review of PI3K Inhibitors in B-Cell Malignancies.

Laura Cannon, Emmeline C Academia, Ashley E Glode.

The phosphoinositide 3-kinase (PI3K) pathway plays a primary role in cellular proliferation and metabolism. Inhibition of the PI3K pathway is an emerging area of drug development and cancer research. Idelalisib, copanlisib, and duvelisib are currently the only U.S. Food & Drug Administration-approved PI3K inhibitors available for use in hematologic malignancies. These PI3K inhibitors differ in their recommended indications, selectivity of PI3K isoforms, dosing, and potential toxicities. Several ongoing studies are aiming to expand the use of such drugs and identify unique combination regimens. This article discusses the current data supporting their place in therapy for B-cell malignancies, management of adverse events, and the clinical implications for advanced practitioners for the commercially available PI3K inhibitors.

DOI: https://doi.org/10.6004/jadpro.2019.10.7.7
Cancer Cell. 2021 Jan 05. pii: S1535-6108(20)30609-7. [Epub ahead of print]

An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence.

Eugen Dhimolea, Ricardo de Matos Simoes, Dhvanir Kansara, Aziz Al'Khafaji, Juliette Bouyssou, Xiang Weng, Shruti Sharma, Joseline Raja, Pallavi Awate, Ryosuke Shirasaki, Huihui Tang, Brian J Glassner, Zhiyi Liu, Dong Gao, Jordan Bryan, Samantha Bender, Jennifer Roth, Michal Scheffer, Rinath Jeselsohn, Nathanael S Gray, Irene Georgakoudi, Francisca Vazquez, Aviad Tsherniak, Yu Chen, Alana Welm, Cihangir Duy, Ari Melnick, Boris Bartholdy, Myles Brown, Aedin C Culhane, Constantine S Mitsiades.

  Treatment-persistent residual tumors impede curative cancer therapy. To understand this cancer cell state we generated models of treatment persistence that simulate the residual tumors. We observe that treatment-persistent tumor cells in organoids, xenografts, and cancer patients adopt a distinct and reversible transcriptional program resembling that of embryonic diapause, a dormant stage of suspended development triggered by stress and associated with suppressed Myc activity and overall biosynthesis. In cancer cells, depleting Myc or inhibiting Brd4, a Myc transcriptional co-activator, attenuates drug cytotoxicity through a dormant diapause-like adaptation with reduced apoptotic priming. Conversely, inducible Myc upregulation enhances acute chemotherapeutic activity. Maintaining residual cells in dormancy after chemotherapy by inhibiting Myc activity or interfering with the diapause-like adaptation by inhibiting cyclin-dependent kinase 9 represent potential therapeutic strategies against chemotherapy-persistent tumor cells. Our study demonstrates that cancer co-opts a mechanism similar to diapause with adaptive inactivation of Myc to persist during treatment.

Keywords:  CDK9; CRISPR; MYC; adaptation to stress; breast cancer; cancer; diapause; drug persistence; prostate cancer; residual tumor

DOI:  https://doi.org/10.1016/j.ccell.2020.12.002
Cell Stem Cell. 2021 Jan 07. pii: S1934-5909(20)30596-8. [Epub ahead of print]28(1): 20-32

Computational Stem Cell Biology: Open Questions and Guiding Principles.

Patrick Cahan, Davide Cacchiarelli, Sara-Jane Dunn, Martin Hemberg, Susana M Chuva de Sousa Lopes, Samantha A Morris, Owen J L Rackham, Antonio Del Sol, Christine A Wells.

Computational biology is enabling an explosive growth in our understanding of stem cells and our ability to use them for disease modeling, regenerative medicine, and drug discovery. We discuss four topics that exemplify applications of computation to stem cell biology: cell typing, lineage tracing, trajectory inference, and regulatory networks. We use these examples to articulate principles that have guided computational biology broadly and call for renewed attention to these principles as computation becomes increasingly important in stem cell biology. We also discuss important challenges for this field with the hope that it will inspire more to join this exciting area.

DOI: https://doi.org/10.1016/j.stem.2020.12.012
Elife. 2021 Jan 04. pii: e54618. [Epub ahead of print]10

Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium.

Madeline Sandoval, Zhe Ying, Slobodan Beronja.

  Skin epithelium can accumulate a high burden of oncogenic mutations without morphological or functional consequences. To investigate the mechanism of oncogenic tolerance, we induced HrasG12V in single murine epidermal cells and followed them long-term. We observed that HrasG12V promotes an early and transient clonal expansion driven by increased progenitor renewal that is replaced with an increase in progenitor differentiation leading to reduced growth. We attribute this dynamic effect to emergence of two populations within oncogenic clones: renewing progenitors along the edge and differentiating ones within the central core. As clone expansion is accompanied by progressive enlargement of the core and diminishment of the edge compartment, the intra-clonal competition between the two populations results in stabilized oncogenic growth. To identify the molecular mechanism of HrasG12V-driven differentiation, we screened known Ras-effector in vivo, and identified Rassf5 as a novel regulator of progenitor fate choice that is necessary and sufficient for oncogene-specific differentiation.

Keywords:  cancer biology; mouse; regenerative medicine; stem cells

DOI:  https://doi.org/10.7554/eLife.54618
Oncogene. 2021 Jan 08.

β-Trcp and CK1δ-mediated degradation of LZTS2 activates PI3K/AKT signaling to drive tumorigenesis and metastasis in hepatocellular carcinoma.

Yanwei Lu, Xudong Li, Hongli Liu, Jun Xue, Zhen Zeng, Xiaorong Dong, Tao Zhang, Gang Wu, Kunyu Yang, Shuangbing Xu.

Distant metastasis is the leading cause of treatment failure in patients with hepatocellular carcinoma (HCC). However, the underlying mechanisms have not been fully elucidated. Here, we report that Leucine zipper tumor suppressor 2 (LZTS2) is downregulated and correlated with poor prognosis in HCC. Furthermore, we provide evidence that LZTS2 associates with p85 to inhibit the activation of PI3K/AKT signaling and impairs HCC tumorigenesis and metastasis in vitro and in vivo. Moreover, we identify LZTS2 as a bona fide substrate of the E3 ligase β-Trcp and protein kinase CK1δ, which are responsible for the ubiquitination and degradation of LZTS2. Importantly, we show that the β-Trcp and CK1δ-mediated degradation of LZTS2 promotes HCC progression and metastasis by activating PI3K/AKT signaling. Collectively, our study not only illustrates the roles of LZTS2 in regulating HCC tumorigenesis and metastasis but also reveals a novel posttranslational modification of LZTS2 by β-Trcp and CK1δ, indicating that the β-Trcp/CK1δ/LZTS2/PI3K axis may be a novel oncogenic driver involved in HCC progression and metastasis.

DOI: https://doi.org/10.1038/s41388-020-01596-2