bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2020‒04‒19
eleven papers selected by
Ralitsa Radostinova Madsen
University College London Cancer Institute

  1. Front Oncol. 2020 ;10 360
      The phosphatidylinositide 3 kinases (PI3Ks) and their downstream mediators AKT and mammalian target of rapamycin (mTOR) are central regulators of glycolysis, cancer metabolism, and cancer cell proliferation. At the molecular level, PI3K signaling involves the generation of the second messenger lipids phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] and phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2]. There is increasing evidence that PI(3,4)P2 is not only the waste product for the removal of PI(3,4,5)P3 but can also act as a signaling molecule. The selective cellular functions for PI(3,4)P2 independent of PI(3,4,5)P3 have been recently described, including clathrin-mediated endocytosis and mTOR regulation. However, the specific spatiotemporal dynamics and signaling role of PI3K minor lipid messenger PI(3,4)P2 are not well-understood. This review aims at highlighting the biological functions of this lipid downstream of phosphoinositide kinases and phosphatases and its implication in cancer metabolism.
    Keywords:  AKT; INPP4; PI3K; PTEN; cancer biology; cancer metabolism; phosphatases; phosphoinositide
  2. Cell. 2020 Apr 16. pii: S0092-8674(20)30346-9. [Epub ahead of print]181(2): 236-249
      Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.
    Keywords:  AI; Cancer Moonshot; Human Tumor Atlas; cancer transitions; data integration; data visualization; metastasis; pre-cancer; resistance; single-cell genomics; spatial genomics; spatial imaging; tumor
  3. Cell Rep. 2020 Apr 14. pii: S2211-1247(20)30404-6. [Epub ahead of print]31(2): 107514
      Cells rely on input from extracellular growth factors to control their proliferation during development and adult homeostasis. Such mitogenic inputs are transmitted through multiple signaling pathways that synergize to precisely regulate cell cycle entry and progression. Although the architecture of these signaling networks has been characterized in molecular detail, their relative contribution, especially at later cell cycle stages, remains largely unexplored. By combining quantitative time-resolved measurements of fluorescent reporters in untransformed human cells with targeted pharmacological inhibitors and statistical analysis, we quantify epidermal growth factor (EGF)-induced signal processing in individual cells over time and dissect the dynamic contribution of downstream pathways. We define signaling features that encode information about extracellular ligand concentrations and critical time windows for inducing cell cycle transitions. We show that both extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) activity are necessary for initial cell cycle entry, whereas only PI3K affects the duration of S phase at later stages of mitogenic signaling.
    Keywords:  MAPK pathway; PI3K pathway; cell-cycle; information theory; mitogenic signaling; scRNA-seq; signaling dynamics; single-cell analysis; time-lapse microscopy
  4. Cancer Cell. 2020 Apr 13. pii: S1535-6108(20)30154-9. [Epub ahead of print]37(4): 431-442
      Prospective molecular characterization of cancer has enabled physicians to define the genomic changes of each patient's tumor in real time and select personalized therapies based on these detailed portraits. Despite the promise of such an approach, previously unrecognized biological and therapeutic complexity is emerging. Here, we synthesize lessons learned and discuss the steps required to extend the benefits of genome-driven oncology, including proposing strategies for improved drug design, more nuanced patient selection, and optimized use of available therapies. Finally, we suggest ways that next-generation genome-driven clinical trials can evolve to accelerate our understanding of cancer biology and improve patient outcomes.
    Keywords:  clinical trial design; drug development; genome-driven oncology; precision oncology
  5. Immunity. 2020 Apr 14. pii: S1074-7613(20)30126-6. [Epub ahead of print]52(4): 650-667.e10
      Appropriate balance of T helper 17 (Th17) and regulatory T (Treg) cells maintains immune tolerance and host defense. Disruption of Th17-Treg cell balance is implicated in a number of immune-mediated diseases, many of which display dysregulation of the insulin-like growth factor (IGF) system. Here, we show that, among effector T cell subsets, Th17 and Treg cells selectively expressed multiple components of the IGF system. Signaling through IGF receptor (IGF1R) activated the protein kinase B-mammalian target of rapamycin (AKT-mTOR) pathway, increased aerobic glycolysis, favored Th17 cell differentiation over that of Treg cells, and promoted a heightened pro-inflammatory gene expression signature. Group 3 innate lymphoid cells (ILC3s), but not ILC1s or ILC2s, were similarly responsive to IGF signaling. Mice with deficiency of IGF1R targeted to T cells failed to fully develop disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Thus, the IGF system represents a previously unappreciated pathway by which type 3 immunity is modulated and immune-mediated pathogenesis controlled.
    Keywords:  CD4 T cell; EAE; IGF1R; Th17; Treg; insulin-like growth factor; multiple sclerosis
  6. Autophagy. 2020 Apr 15. 1-3
      Macroautophagy/autophagy is an evolutionarily conserved cellular degradation and recycling process that is tightly regulated by external stimuli, diet, and stress. Our recent findings suggest that in C. elegans, a nutrient sensing pathway mediated by MTORC2 (mechanistic target of rapamycin kinase complex 2) and its downstream effector kinase SGK-1 (serum- and glucocorticoid-inducible kinase homolog 1) suppresses autophagy, involving mitophagy. Induced autophagy/mitophagy in MTORC2-deficient animals slows down development and impairs reproduction independently of the SGK-1 effectors DAF-16/FOXO and SKN-1/NFE2L2/NRF2. In this punctum, we discuss how TORC2-SGK-1 signaling might regulate autophagic turnover and its impact on mitochondrial homeostasis via linking mitochondria-derived reactive oxygen species (mtROS) production to mitophagic turnover.
    Keywords:  Autophagy; MTORC (mechanistic target of rapamycin kinase complex); ROS (reactive oxygen species); SGK-1 (serum- and glucocorticoid-inducible kinase homolog 1); VDAC1 (voltage dependent anion channel 1); mitophagy
  7. Nature. 2020 Apr;580(7803): 402-408
      Global insights into cellular organization and genome function require comprehensive understanding of the interactome networks that mediate genotype-phenotype relationships1,2. Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. The integration of HuRI with genome3, transcriptome4 and proteome5 data enables cellular function to be studied within most physiological or pathological cellular contexts. We demonstrate the utility of HuRI in identifying the specific subcellular roles of protein-protein interactions. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms that might underlie tissue-specific phenotypes of Mendelian diseases. HuRI is a systematic proteome-wide reference that links genomic variation to phenotypic outcomes.
  8. Cancer Cell. 2020 Apr 13. pii: S1535-6108(20)30149-5. [Epub ahead of print]37(4): 496-513
      Estrogen receptor-positive (ER+) breast cancer is the most common breast cancer subtype. Treatment of ER+ breast cancer comprises interventions that suppress estrogen production and/or target the ER directly (overall labeled as endocrine therapy). While endocrine therapy has considerably reduced recurrence and mortality from breast cancer, de novo and acquired resistance to this treatment remains a major challenge. An increasing number of mechanisms of endocrine resistance have been reported, including somatic alterations, epigenetic changes, and changes in the tumor microenvironment. Here, we review recent advances in delineating mechanisms of resistance to endocrine therapies and potential strategies to overcome such resistance.
    Keywords:  ESR1; SERD; SERM; aromatase inhibitor; breast cancer; endocrine resistance; estrogen receptor
  9. Cell. 2020 Apr 15. pii: S0092-8674(20)30332-9. [Epub ahead of print]
      Adoptive transfer of genetically modified immune cells holds great promise for cancer immunotherapy. CRISPR knockin targeting can improve cell therapies, but more high-throughput methods are needed to test which knockin gene constructs most potently enhance primary cell functions in vivo. We developed a widely adaptable technology to barcode and track targeted integrations of large non-viral DNA templates and applied it to perform pooled knockin screens in primary human T cells. Pooled knockin of dozens of unique barcoded templates into the T cell receptor (TCR)-locus revealed gene constructs that enhanced fitness in vitro and in vivo. We further developed pooled knockin sequencing (PoKI-seq), combining single-cell transcriptome analysis and pooled knockin screening to measure cell abundance and cell state ex vivo and in vivo. This platform nominated a novel transforming growth factor β (TGF-β) R2-41BB chimeric receptor that improved solid tumor clearance. Pooled knockin screening enables parallelized re-writing of endogenous genetic sequences to accelerate discovery of knockin programs for cell therapies.
    Keywords:  CRISPR; cell therapy; human T cell; knockins; pooled screen; single-cell RNA-seq
  10. Clin Breast Cancer. 2020 Mar 12. pii: S1526-8209(19)30756-6. [Epub ahead of print]
      BACKGROUND: Breast cancer stem cells (BCSCs) play important role(s) in the development and progression of invasive duct carcinoma (IDC). We assessed the role of BCSC marker expression and the number of mammospheres in cultures of breast cancer (BC) tissues and correlated these data to relevant clinicopathologic features of the patients and overall survival (OS).METHODS: Fresh tumor tissue samples were collected from 44 Egyptian female patients with IDC of the breast and 25 healthy women undergoing reduction mammoplasty as a control. The mammosphere number and the RNA expression levels of some cancer stem cell-related genes (PTEN, PI3K, AKT, Wnt, and β-catenin) were assessed by reverse-transcriptase polymerase chain reaction at different stages of BCSC differentiation compared with control samples.
    RESULTS: The number of CD44+CD24-/low cells associated significantly at the end of culture with the expression level of Wnt, β-catenin, and distant metastasis (P < .001, P = .015 and P = .003, respectively). There was significant association between the mammosphere number and CD44+CD24-/low cells as well as AKT expression (P = .040 and .021, respectively). PTEN messenger RNA expressed significantly in BC (P < .05). Wnt-RNA expression associated significantly with high tumor stage, positive lymph node status, Her2-neu overexpression, and metastasis (P = .009, .012, .026, and .001, respectively), whereas OS associated significantly with distant metastasis, Wnt, and PTEN expressions (P < .001, P = .001, P = .014, respectively).
    CONCLUSION: BCSCs and their related genes (PTEN, PI3K, AKT, Wnt, and β-catenin) play important roles in the development and progression of BC and they can be used as potential prognostic and predictive biomarkers for patients with BC or as target therapy.
    Keywords:  AKT; BCSCs; Mammospheres; PI3K; PTEN; Wnt; β-catenin
  11. Biochem J. 2020 Apr 16. pii: BCJ20190754. [Epub ahead of print]
      Osteosarcoma and chondrosarcoma are sarcomas of the bone and the cartilage that are primarily treated by surgical intervention combined with high toxicity chemotherapy. In search of alternative metabolic approaches to address the challenges in treating bone sarcomas, we assessed the growth dependence of these cancers on leucine, one of the branched chain amino acids (BCAAs), and BCAA metabolism. Tumor biopsies from bone sarcoma patients revealed differential expression of BCAA metabolic enzymes. The cytosolic branched chain aminotransferase (BCATc) that is commonly overexpressed in cancer cells, was downregulated in chondrosarcoma (SW1353) in contrast to osteosarcoma (143B) cells that expressed both BCATc and its mitochondrial isoform BCATm. Treating SW1353cells with gabapentin, a selective inhibitor of BCATc, further revealed that these cells failed to respond to gabapentin. Application of the structural analog of leucine, N-acetyl-leucine amide (NALA) to disrupt leucine uptake, indicated that all bone sarcoma cells used leucine to support their energy metabolism and biosynthetic demands. This was evident from the increased activity of the energy sensor AMP-activated protein kinase (AMPK), downregulation of complex 1 of the mammalian target of rapamycin (mTORC1), and reduced cell viability in response to NALA.  The observed changes were most profound in the 143B cells, which appeared highly dependent on cytosolic and mitochondrial BCAA metabolism. This study thus demonstrates that bone sarcomas rely on leucine and BCAA metabolism for energy and growth; however, the differential expression of BCAA enzymes and the presence of other carbon sources may dictate how efficiently these cancer cells take advantage of BCAA metabolism.
    Keywords:  BCAAs; BCATc; BCATm; Leucine; chondrosarcoma; osteosarcoma