bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2021–01–17
six papers selected by
Ralitsa Radostinova Madsen, University College London
  1. The role of the PIK3CA gene in the development and aging of the brain.
  2. Multiple signaling pathways are essential for synapse formation induced by synaptic adhesion molecules.
  3. Connecting Timescales in Biology: Can Early Dynamical Measurements Predict Long-Term Outcomes?
  4. Imaging dynamic mTORC1 pathway activity in vivo reveals marked shifts that support time-specific inhibitor therapy in AML.
  5. In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1.
  6. Targeting metastatic cancer.
  1. Sci Rep. 2021 Jan 11. 11(1): 291
    The role of the PIK3CA gene in the development and aging of the brain.
    Shaozhen Xie, Jing Ni, Hanbing Guo, Victor Luu, Yanzhi Wang, Jean J Zhao, Thomas M Roberts.
      The CLOVES syndrome is an overgrowth disease arising from mosaic activating somatic mutations in the PIK3CA gene. These mutations occur during fetal development producing malformation and overgrowth of a variety of tissues. It has recently been shown that treatment with low doses of a selective inhibitor of Class I PI3K catalytic subunit p110α, the protein product of the PIK3CA gene, can yield dramatic therapeutic benefits for patients with CLOVES and PROS (a spectrum of PIK3CA-related overgrowth syndromes). To assess the long-term effects of moderate loses of p110α activity, we followed development and growth of mice with heterozygous loss of p110α (Pik3ca+/-) over their entire lifetimes, paying particular attention to effects on the brain. While homozygous deletion of the Pik3ca gene is known to result in early embryonic lethality, these Pik3ca+/- mice displayed a longer lifespan compared to their wild-type littermates. These mice appeared normal, exhibited no obvious behavioral abnormalities, and no body weight changes. However, their brains showed a significant reduction in size and weight. Notably, mice featuring deletion of one allele of Pik3ca only in the brain also showed gradually reduced brain size and weight. Mechanistically, either deletion of p110α or pharmacological inhibition of p110α activity reduced neurosphere size, but not numbers, in vitro, suggesting that p110α activity is critical for neuronal stem cells. The phenotypes observed in our two genetically engineered mouse models suggest that the sustained pharmacological inhibition of the PIK3CA activity in human patients might have both beneficial and harmful effects, and future treatments may need to be deployed in a way to avoid or minimize adverse effects.
    DOI:  https://doi.org/10.1038/s41598-020-79416-6
  2. Proc Natl Acad Sci U S A. 2021 Jan 19. pii: e2000173118. [Epub ahead of print]118(3):
    Multiple signaling pathways are essential for synapse formation induced by synaptic adhesion molecules.
    Xian Jiang, Richard Sando, Thomas C Südhof.
      Little is known about the cellular signals that organize synapse formation. To explore what signaling pathways may be involved, we employed heterologous synapse formation assays in which a synaptic adhesion molecule expressed in a nonneuronal cell induces pre- or postsynaptic specializations in cocultured neurons. We found that interfering pharmacologically with microtubules or actin filaments impaired heterologous synapse formation, whereas blocking protein synthesis had no effect. Unexpectedly, pharmacological inhibition of c-jun N-terminal kinases (JNKs), protein kinase-A (PKA), or AKT kinases also suppressed heterologous synapse formation, while inhibition of other tested signaling pathways-such as MAP kinases or protein kinase C-did not alter heterologous synapse formation. JNK and PKA inhibitors suppressed formation of both pre- and postsynaptic specializations, whereas AKT inhibitors impaired formation of post- but not presynaptic specializations. To independently test whether heterologous synapse formation depends on AKT signaling, we targeted PTEN, an enzyme that hydrolyzes phosphatidylinositol 3-phosphate and thereby prevents AKT kinase activation, to postsynaptic sites by fusing PTEN to Homer1. Targeting PTEN to postsynaptic specializations impaired heterologous postsynaptic synapse formation induced by presynaptic adhesion molecules, such as neurexins and additionally decreased excitatory synapse function in cultured neurons. Taken together, our results suggest that heterologous synapse formation is driven via a multifaceted and multistage kinase network, with diverse signals organizing pre- and postsynaptic specializations.
    Keywords:  Pten; adhesion molecules; c-jun N-terminal kinase; signal transduction; synapse formation
    DOI:  https://doi.org/10.1073/pnas.2000173118
  3. Trends Cancer. 2021 Jan 12. pii: S2405-8033(20)30335-6. [Epub ahead of print]
    Connecting Timescales in Biology: Can Early Dynamical Measurements Predict Long-Term Outcomes?
    Michael Tsabar, Scott B Lovitch, Ashwini Jambhekar, Galit Lahav.
      Prediction of long-term outcomes from short-term measurements remains a fundamental challenge. Quantitative assessment of signaling dynamics, and the resulting transcriptomic and proteomic responses, has yielded fundamental insights into cellular outcomes. However, the utility of these measurements is limited by their short timescale (hours to days), while the consequences of these events frequently unfold over longer timescales. Here, we discuss the predictive power of static and dynamic measurements, drawing examples from fields that have harnessed the predictive capabilities of such measurements. We then explore potential approaches to close this timescale gap using complementary measurements and computational approaches, focusing on the example of dynamic measurements of signaling factors and their impacts on cellular outcomes.
    Keywords:  cell fate; markers; outcomes; p53; signaling dynamics; timescale
    DOI:  https://doi.org/10.1016/j.trecan.2020.12.008
  4. Nat Commun. 2021 01 11. 12(1): 245
    Imaging dynamic mTORC1 pathway activity in vivo reveals marked shifts that support time-specific inhibitor therapy in AML.
    Toshihiko Oki, Francois Mercier, Hiroki Kato, Yookyung Jung, Thomas O McDonald, Joel A Spencer, Michael C Mazzola, Nick van Gastel, Charles P Lin, Franziska Michor, Toshio Kitamura, David T Scadden.
      Acute myeloid leukemia (AML) is a high remission, high relapse fatal blood cancer. Although mTORC1 is a master regulator of cell proliferation and survival, its inhibitors have not performed well as AML treatments. To uncover the dynamics of mTORC1 activity in vivo, fluorescent probes are developed to track single cell proliferation, apoptosis and mTORC1 activity of AML cells in the bone marrow of live animals and to quantify these activities in the context of microanatomical localization and intra-tumoral heterogeneity. When chemotherapy drugs commonly used clinically are given to mice with AML, apoptosis is rapid, diffuse and not preferentially restricted to anatomic sites. Dynamic measurement of mTORC1 activity indicated a decline in mTORC1 activity with AML progression. However, at the time of maximal chemotherapy response, mTORC1 signaling is high and positively correlated with a leukemia stemness transcriptional profile. Cell barcoding reveals the induction of mTORC1 activity rather than selection of mTORC1 high cells and timed inhibition of mTORC1 improved the killing of AML cells. These data define the real-time dynamics of AML and the mTORC1 pathway in association with AML growth, response to and relapse after chemotherapy. They provide guidance for timed intervention with pathway-specific inhibitors.
    DOI:  https://doi.org/10.1038/s41467-020-20491-8
  5. Proc Natl Acad Sci U S A. 2021 Jan 05. pii: e2010054118. [Epub ahead of print]118(1):
    In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1.
    Christian Duellberg, Albert Auer, Nikola Canigova, Katrin Loibl, Martin Loose.
      The differentiation of cells depends on a precise control of their internal organization, which is the result of a complex dynamic interplay between the cytoskeleton, molecular motors, signaling molecules, and membranes. For example, in the developing neuron, the protein ADAP1 (ADP-ribosylation factor GTPase-activating protein [ArfGAP] with dual pleckstrin homology [PH] domains 1) has been suggested to control dendrite branching by regulating the small GTPase ARF6. Together with the motor protein KIF13B, ADAP1 is also thought to mediate delivery of the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to the axon tip, thus contributing to PIP3 polarity. However, what defines the function of ADAP1 and how its different roles are coordinated are still not clear. Here, we studied ADAP1's functions using in vitro reconstitutions. We found that KIF13B transports ADAP1 along microtubules, but that PIP3 as well as PI(3,4)P2 act as stop signals for this transport instead of being transported. We also demonstrate that these phosphoinositides activate ADAP1's enzymatic activity to catalyze GTP hydrolysis by ARF6. Together, our results support a model for the cellular function of ADAP1, where KIF13B transports ADAP1 until it encounters high PIP3/PI(3,4)P2 concentrations in the plasma membrane. Here, ADAP1 disassociates from the motor to inactivate ARF6, promoting dendrite branching.
    Keywords:  PIP3 signaling; in vitro reconstitution; microtubule transport; neuronal development; small GTPases
    DOI:  https://doi.org/10.1073/pnas.2010054118
  6. Nat Med. 2021 01;27(1): 34-44
    Targeting metastatic cancer.
    Karuna Ganesh, Joan Massagué.
      Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. Recent work has uncovered the unique biology of metastasis-initiating cells that results in tumor growth in distant organs, evasion of immune surveillance and co-option of metastatic microenvironments. Here we review recent progress that is enabling therapeutic advances in treating both micro- and macrometastases. Such insights were gained from cancer sequencing, mechanistic studies and clinical trials, including of immunotherapy. These studies reveal both the origins and nature of metastases and identify new opportunities for developing more effective strategies to target metastatic relapse and improve patient outcomes.
    DOI:  https://doi.org/10.1038/s41591-020-01195-4
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