bims-cagime 2020-08-02 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2020–08–02
thirty-one papers selected by
Kıvanç Görgülü, Technical University of Munich

Oncogenic splicing regulated by phase separation.
Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat.
Tuft Cells Inhibit Pancreatic Tumorigenesis in Mice by Producing Prostaglandin D2.
Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention.
Characterizing the ecological and evolutionary dynamics of cancer.
Molecular epidemiology and diagnostics of KRAS mutations in human cancer.
JNK signaling contributes to skeletal muscle wasting and protein turnover in pancreatic cancer cachexia.
Phase Separation in Membrane Biology: The Interplay between Membrane-Bound Organelles and Membraneless Condensates.
Determinants of Endoplasmic Reticulum-to-Lipid Droplet Protein Targeting.
The Myc and Ras Partnership in Cancer: Indistinguishable Alliance or Contextual Relationship?
Recent Experiments Support a Microemulsion Origin of Plasma Membrane Domains: Dependence of Domain Size on Physical Parameters.
3D mapping and accelerated super-resolution imaging of the human genome using in situ sequencing.
Dihydroxyacetone phosphate signals glucose availability to mTORC1.
The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic.
NPC-phagy: selective autophagy of the nuclear pore complexes.
Mechanisms of stretch-mediated skin expansion at single-cell resolution.
Combined Proteomic and Genetic Interaction Mapping Reveals New RAS Effector Pathways and Susceptibilities.
Molecular dynamics study of lipid bilayers modeling outer and inner leaflets of plasma membranes of mouse hepatocytes. I. Differences in physicochemical properties between the two leaflets.
IMPACT: Imaging phospholipase d activity with clickable alcohols via transphosphatidylation.
Deep learning-based image analysis methods for brightfield-acquired multiplex immunohistochemistry images.
The insufficiency of ATG4A in macroautophagy.
More than just a garbage can: emerging roles of the lysosome as an anabolic organelle in skeletal muscle.
Cyclin D-CDK4/6 functions in cancer.
A Cost Effective and Adaptable Scratch Migration Assay.
Induction of Ordered Lipid Raft Domain Formation by Loss of Lipid Asymmetry.
Maintaining social contacts: The physiological relevance of organelle interactions.
Lysosomal activity regulates Caenorhabditis elegans mitochondrial dynamics through vitamin B12 metabolism.
A Phase I Study of Dinaciclib in Combination With MK-2206 in Patients With Advanced Pancreatic Cancer.
The Secret Lives of Fluorescent Membrane Probes as Revealed by Molecular Dynamics Simulations.
Lipid composition of the cancer cell membrane.
DysRegSig: an R package for identifying gene dysregulations and building mechanistic signatures in cancer.

Nat Cell Biol. 2020 Jul 27.

Oncogenic splicing regulated by phase separation.

Bo Liu, Omar Abdel-Wahab.

DOI: https://doi.org/10.1038/s41556-020-0553-5
Elife. 2020 Jul 28. pii: e55909. [Epub ahead of print]9

Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat.

Lisa R Beutler, Timothy V Corpuz, Jamie S Ahn, Seher Kosar, Weimin Song, Yiming Chen, Zachary A Knight.

  Body weight is regulated by interoceptive neural circuits that track energy need, but how the activity of these circuits is altered in obesity remains poorly understood. Here we describe the in vivo dynamics of hunger-promoting AgRP neurons during the development of diet-induced obesity in mice. We show that high-fat diet attenuates the response of AgRP neurons to an array of nutritionally-relevant stimuli including food cues, intragastric nutrients, cholecystokinin and ghrelin. These alterations are are specific to dietary fat but not carbohydrate or protein. Subsequent weight loss restores the responsiveness of AgRP neurons to exterosensory cues but fails to rescue their sensitivity to gastrointestinal hormones or nutrients. These findings reveal that obesity triggers broad dysregulation of hypothalamic hunger neurons that is incompletely reversed by weight loss and may contribute to the difficulty of maintaining a reduced weight.

Keywords:  mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.55909
Gastroenterology. 2020 Jul 24. pii: S0016-5085(20)34999-4. [Epub ahead of print]

Tuft Cells Inhibit Pancreatic Tumorigenesis in Mice by Producing Prostaglandin D2.

Kathleen E DelGiorno, Chi-Yeh Chung, Vera Vavinskaya, H Carlo Maurer, Sammy Weiser Novak, Nikki K Lytle, Zhibo Ma, Rajshekhar R Giraddi, Dezhen Wang, Linjing Fang, Razia F Naeem, Leonardo R Andrade, Wahida H Ali, Hubert Tseng, Crystal Tsui, Vikas B Gubbala, Maya Ridinger-Saison, Makoto Ohmoto, Galina A Erikson, Carolyn O'Connor, Maxim Nikolaievich Shokhirev, Nasun Hah, Yoshihiro Urade, Ichiro Matsumoto, Susan M Kaech, Pankaj K Singh, Uri Manor, Kenneth P Olive, Geoffrey M Wahl.

   BACKGROUND & AIMS: Development of pancreatic ductal adenocarcinoma (PDA) involves acinar to ductal metaplasia and genesis of tuft cells. It has been a challenge to study these rare cells due to lack of animal models. We investigated the role of tuft cells in pancreatic tumorigenesis.
METHODS: We performed studies with LSL-KrasG12D/+; Ptf1aCre/+ mice (KC, develop pancreatic tumors), KC mice crossed with mice with pancreatic disruption of Pou2f3 (KPouC mice, do not develop Tuft cells), or mice with pancreatic disruption of the hematopoietic prostaglandin D synthase gene (Hpgds, KHC mice), and wild-type mice. Mice were allowed to age or were given caerulein to induce pancreatitis; pancreata were collected and analyzed by histology, immunohistochemistry, RNA sequencing, ultrastructural microscopy, and metabolic profiling. We performed laser-capture dissection and RNA sequencing analysis of pancreatic tissues from 26 patients with pancreatic intraepithelial neoplasias (PanINs), 19 patients with intraductal papillary mucinous neoplasms (IPMN), and 197 patients with PDA.
RESULTS: Pancreata from KC mice had increased formation of tuft cells and higher levels of prostaglandin D2 than wild-type mice. Pancreas-specific deletion of POU2F3 in KC mice (KPouC mice) resulted in a loss of tuft cells and accelerated tumorigenesis. KPouC mice had increased fibrosis and activation of immune cells following administration of caerulein. Pancreata from KPouC and KHC mice had significantly lower levels of PGD2, compared with KC mice, and significantly increased numbers of PanINs and PDAs. KPouC and KHC mice had increased pancreatic injury, following administration of caerulein, significantly less normal tissue, more extracellular matrix deposition, and higher PanIN grade than KC mice. Human PanIN and IPMN had gene expression signatures associated with tuft cells and increased expression of Hpgds mRNA compared with PDA.
CONCLUSIONS: In mice with KRAS-induced pancreatic tumorigenesis, loss of tuft cells accelerates tumorigenesis and increases the severity of caerulein-induced pancreatic injury, via decreased production of PGD2. These data are consistent with the hypothesis that tuft cells are a metaplasia-induced tumor attenuating cell type.

Keywords:  COX1; COX2; eicosanoids; inflammation

DOI:  https://doi.org/10.1053/j.gastro.2020.07.037
Adv Drug Deliv Rev. 2020 Jul 22. pii: S0169-409X(20)30097-1. [Epub ahead of print]

Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention.

Lisa Butler, Ylenia Perone, Jonas Dehairs, Leslie E Lupien, Vincent de Laat, Ali Talebi, Massimo Loda, William B Kinlaw, Johannes V Swinnen.

  With the advent of effective tools to study lipids, including mass spectrometry-based lipidomics, lipids are emerging as central players in cancer biology. Lipids function as essential building blocks for membranes, serve as fuel to drive energy-demanding processes and play a key role as signaling molecules and as regulators of numerous cellular functions. Not unexpectedly, cancer cells, as well as other cell types in the tumor microenvironment, exploit various ways to acquire lipids and extensively rewire their metabolism as part of a plastic and context-dependent metabolic reprogramming that is driven by both oncogenic and environmental cues. The resulting changes in the fate and composition of lipids help cancer cells to thrive in a changing microenvironment by supporting key oncogenic functions and cancer hallmarks, including cellular energetics, promoting feedforward oncogenic signaling, resisting oxidative and other stresses, regulating intercellular communication and immune responses. Supported by the close connection between altered lipid metabolism and the pathogenic process, specific lipid profiles are emerging as unique disease biomarkers, with diagnostic, prognostic and predictive potential. Multiple pre-clinical studies illustrate the translational promise of exploiting lipid metabolism in cancer, and critically, have shown context dependent actionable vulnerabilities that can be rationally targeted, particularly in combinatorial approaches. Moreover, lipids themselves can be used as membrane disrupting agents or as key components of nanocarriers of various therapeutics. With a number of pre-clinical compounds and strategies that are approaching clinical trials, we are at the doorstep of exploiting a hitherto underappreciated hallmark of cancer and promising target in the oncologist's strategy to combat cancer.

Keywords:  De novo lipogenesis; Fatty acid synthesis; Fatty acids; Lipid droplets; Lipid uptake; Lipidomics; Membrane lipids; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.addr.2020.07.013
Nat Genet. 2020 Jul 27.

Characterizing the ecological and evolutionary dynamics of cancer.

Nastaran Zahir, Ruping Sun, Daniel Gallahan, Robert A Gatenby, Christina Curtis.

Tumor initiation and progression are somatic evolutionary processes driven by the accumulation of genetic alterations, some of which confer selective fitness advantages to the host cell. This gene-centric model has shaped the field of cancer biology and advanced understanding of cancer pathophysiology. Importantly, however, each genotype encodes diverse phenotypic traits that permit acclimation to varied microenvironmental conditions. Epigenetic and transcriptional changes also contribute to the heritable phenotypic variation required for evolution. Additionally, interactions between cancer cells and surrounding stromal and immune cells through autonomous and non-autonomous signaling can influence competition for survival. Therefore, a mechanistic understanding of tumor progression must account for evolutionary and ecological dynamics. In this Perspective, we outline technological advances and model systems to characterize tumor progression through space and time. We discuss the importance of unifying experimentation with computational modeling and opportunities to inform cancer control.

DOI: https://doi.org/10.1038/s41588-020-0668-4
Cancer Metastasis Rev. 2020 Jul 29.

Molecular epidemiology and diagnostics of KRAS mutations in human cancer.

Jozsef Timar, Karl Kashofer.

  RAS mutation is the most frequent oncogenic alteration in human cancers. KRAS is the most frequently mutated followed by NRAS. The emblematic KRAS mutant cancers are pancreatic, colorectal, lung adenocarcinomas and urogenital cancers. KRAS mutation frequencies are relatively stable worldwide in various cancer types with the one exception of lung adenocarcinoma. The frequencies of KRAS variant alleles appears cancer type specific, reflecting the various carcinogenic processes. In addition to point mutation KRAS, allelic imbalances are also frequent in human cancers leading to the predominance of a mutant allele. KRAS mutant cancers are characterized by typical, cancer-type-specific co-occurring mutations and distinct gene expression signatures. The heterogeneity of KRAS mutant primary cancers is significant, affecting the variant allele frequency, which could lead to unpredictable branching development in metastases. Selection of minute mutant subclones in the primary tumors or metastases during target therapies can also occur frequently in lung or colorectal cancers leading to acquired resistance. Ultrahigh sensitivity techniques are now routinely available for diagnostic purposes, but the proper determination of mutant allele frequency of KRAS in the primary or metastatic tissues may have larger clinical significance.

Keywords:  Diagnostics; Epidemiology; Human cancer; KRAS mutation; Tumor progression

DOI:  https://doi.org/10.1007/s10555-020-09915-5
Cancer Lett. 2020 Jul 28. pii: S0304-3835(20)30381-5. [Epub ahead of print]

JNK signaling contributes to skeletal muscle wasting and protein turnover in pancreatic cancer cachexia.

Scott E Mulder, Aneesha Dasgupta, Ryan J King, Jaime Abrego, Kuldeep S Attri, Divya Murthy, Surendra K Shukla, Pankaj K Singh.

  Cancer cachexia patients experience significant muscle wasting, which impairs the quality of life and treatment efficacy for patients. Skeletal muscle protein turnover is imparted by increased expression of ubiquitin-proteasome pathway components. Mitogen-activated protein kinases p38 and ERK have been shown to augment E3 ubiquitin ligase expression. Utilizing reverse phase protein arrays, we identified pancreatic cancer cell-conditioned media-induced activation of JNK signaling in myotubes differentiated from C2C12 myoblasts. Inhibition of JNK signaling with SP600125 reduced cancer cell-conditioned media-induced myotube atrophy, myosin heavy chain 2 protein turnover, and mRNA expression of cachexia-specific ubiquitin ligases Trim63 and Fbxo32. Furthermore, utilizing an orthotopic pancreatic cancer cachexia mouse model, we demonstrated that treatment of tumor-bearing mice with SP600125 improved longitudinal measurements forelimb grip strength. Post-necropsy measurements demonstrated that SP600125 treatment rescued body weight, carcass weight, and gastrocnemius muscle weight without impacting tumor growth. JNK inhibitor treatment also rescued myofiber degeneration and reduced the muscle expression of Trim63 and Fbxo32. These data demonstrate that JNK signaling contributes to muscle wasting in cancer cachexia and its inhibition has the potential to be utilized as an anti-cachectic therapy.

Keywords:  Cancer cachexia; JNK signaling; Muscle wasting; Ubiquitin ligases

DOI:  https://doi.org/10.1016/j.canlet.2020.07.025
Dev Cell. 2020 Jul 12. pii: S1534-5807(20)30541-4. [Epub ahead of print]

Phase Separation in Membrane Biology: The Interplay between Membrane-Bound Organelles and Membraneless Condensates.

Yan G Zhao, Hong Zhang.

  In eukaryotic cells, various membrane-bound organelles compartmentalize diverse cellular activities in a spatially and temporally controlled manner. Numerous membraneless organelles assembled via liquid-liquid phase separation (LLPS), known as condensates, also facilitate compartmentalization of cellular functions. Emerging evidence shows that these two organelle types interact in many biological processes. Membranes modulate the biogenesis and dynamics of phase-separated condensates by serving as assembly platforms or by forming direct contacts. Phase separation of membrane-associated proteins participates in various trafficking events, such as clustering of vesicles for temporally controlled fusion and storage, and transport of membraneless condensates on membrane-bound organelles. Phase separation also acts in cargo trafficking pathways by sorting and docking cargos for translocon-mediated transport across membranes, by shuttling cargos through the nuclear pore complex, and by triggering the formation of surrounding autophagosomes for delivery to lysosomes. The coordinated actions of membrane-bound and membraneless organelles ensure spatiotemporal control of various cellular functions.

Keywords:  autophagy; condensates; membrane-bound organelles; phase separation; vesicle trafficking

DOI:  https://doi.org/10.1016/j.devcel.2020.06.033
Dev Cell. 2020 Jul 27. pii: S1534-5807(20)30549-9. [Epub ahead of print]

Determinants of Endoplasmic Reticulum-to-Lipid Droplet Protein Targeting.

Maria-Jesus Olarte, Siyoung Kim, Morris E Sharp, Jessica M J Swanson, Robert V Farese, Tobias C Walther.

  Lipid droplet (LD) formation from the endoplasmic reticulum (ER) is accompanied by the targeting and accumulation of specific hydrophobic, membrane-embedded proteins on LDs. The determinants of this process are unknown. Here, we study the hydrophobic membrane motifs of two Drosophila melanogaster proteins, GPAT4 and ALG14, that utilize this pathway, and we identify crucial sequence features that mediate LD accumulation. Molecular dynamics simulations and studies in cells reveal that LD targeting of these motifs requires deeply inserted tryptophans that have lower free energy in the LD oil phase and positively charged residues near predicted hairpin hinges that become less constrained in the LD environment. Analyzing hydrophobic motifs from similar LD-targeting proteins, it appears that the distribution of tryptophan and positively charged residues distinguishes them from non-LD-targeting membrane motifs. Our studies identify specific sequence features and principles of hydrophobic membrane motifs that mediate their accumulation on LDs.

Keywords:  LiveDrop; UDP-N-acetylglucosaminyltransferase subunit; endoplasmic reticulum; glycerol-3-phosphate acyltransferase 4; lipid droplets; protein targeting

DOI:  https://doi.org/10.1016/j.devcel.2020.07.001
Cancer Res. 2020 Jul 30. pii: canres.0787.2020. [Epub ahead of print]

The Myc and Ras Partnership in Cancer: Indistinguishable Alliance or Contextual Relationship?

Wadie Daniel Mahauad-Fernandez, Dean W Felsher.

Myc and Ras are two of the most commonly activated oncogenes in tumorigenesis. Together and independently they regulate many cancer hallmarks including proliferation, apoptosis and self-renewal. Recently, they were shown to cooperate to regulate host tumor microenvironment programs including host immune responses. But, is their partnership always cooperative or do they have distinguishable functions? Here, we provide one perspective that Myc and Ras cooperation depends on the genetic evolution of a particular cancer. This in turn, dictates when they cooperate via overlapping and identifiably distinct cellular and host immune dependent mechanisms that are cancer type specific.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-0787
Membranes (Basel). 2020 Jul 28. pii: E167. [Epub ahead of print]10(8):

Recent Experiments Support a Microemulsion Origin of Plasma Membrane Domains: Dependence of Domain Size on Physical Parameters.

David W Allender, M Schick.

  It is widely, but not universally, believed that the lipids of the plasma membrane are not uniformly distributed, but that "rafts" of sphingolipids and cholesterol float in a "sea" of unsaturated lipids. The physical origin of such heterogeneities is often attributed to a phase coexistence between the two different domains. We argue that this explanation is untenable for several reasons. Further, we note that the results of recent experiments are inconsistent with this picture. However, they are quite consistent with an alternate explanation, namely, that the plasma membrane is a microemulsion of the two kinds of regions. To show this, we briefly review a simplified version of this theory and its phase diagram. We also explicate the dependence of the predicted domain size on four physical parameters. They are the energy cost of gradients in the composition, the spontaneous curvature of the membrane, its bending modulus and its surface tension. Taking values of the latter two from experiment, we obtain domain sizes for several different cell types that vary from 58 to 88 nm.

Keywords:  domain size; microemulsion; phase-separation; plasma membrane; rafts

DOI:  https://doi.org/10.3390/membranes10080167
Nat Methods. 2020 Aug;17(8): 822-832

3D mapping and accelerated super-resolution imaging of the human genome using in situ sequencing.

Huy Q Nguyen, Shyamtanu Chattoraj, David Castillo, Son C Nguyen, Guy Nir, Antonios Lioutas, Elliot A Hershberg, Nuno M C Martins, Paul L Reginato, Mohammed Hannan, Brian J Beliveau, George M Church, Evan R Daugharthy, Marc A Marti-Renom, C-Ting Wu.

There is a need for methods that can image chromosomes with genome-wide coverage, as well as greater genomic and optical resolution. We introduce OligoFISSEQ, a suite of three methods that leverage fluorescence in situ sequencing (FISSEQ) of barcoded Oligopaint probes to enable the rapid visualization of many targeted genomic regions. Applying OligoFISSEQ to human diploid fibroblast cells, we show how four rounds of sequencing are sufficient to produce 3D maps of 36 genomic targets across six chromosomes in hundreds to thousands of cells, implying a potential to image thousands of targets in only five to eight rounds of sequencing. We also use OligoFISSEQ to trace chromosomes at finer resolution, following the path of the X chromosome through 46 regions, with separate studies showing compatibility of OligoFISSEQ with immunocytochemistry. Finally, we combined OligoFISSEQ with OligoSTORM, laying the foundation for accelerated single-molecule super-resolution imaging of large swaths of, if not entire, human genomes.

DOI: https://doi.org/10.1038/s41592-020-0890-0
Nat Metab. 2020 Jul 27.

Dihydroxyacetone phosphate signals glucose availability to mTORC1.

Jose M Orozco, Patrycja A Krawczyk, Sonia M Scaria, Andrew L Cangelosi, Sze Ham Chan, Tenzin Kunchok, Caroline A Lewis, David M Sabatini.

The mechanistic target of rapamycin complex 1 (mTORC1) kinase regulates cell growth by setting the balance between anabolic and catabolic processes. To be active, mTORC1 requires the environmental presence of amino acids and glucose. While a mechanistic understanding of amino acid sensing by mTORC1 is emerging, how glucose activates mTORC1 remains mysterious. Here, we used metabolically engineered human cells lacking the canonical energy sensor AMP-activated protein kinase to identify glucose-derived metabolites required to activate mTORC1 independent of energetic stress. We show that mTORC1 senses a metabolite downstream of the aldolase and upstream of the GAPDH-catalysed steps of glycolysis and pinpoint dihydroxyacetone phosphate (DHAP) as the key molecule. In cells expressing a triose kinase, the synthesis of DHAP from DHA is sufficient to activate mTORC1 even in the absence of glucose. DHAP is a precursor for lipid synthesis, a process under the control of mTORC1, which provides a potential rationale for the sensing of DHAP by mTORC1.

DOI: https://doi.org/10.1038/s42255-020-0250-5
Nature. 2020 Jul 29.

The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic.

Eliran Kadosh, Irit Snir-Alkalay, Avanthika Venkatachalam, Shahaf May, Audrey Lasry, Ela Elyada, Adar Zinger, Maya Shaham, Gitit Vaalani, Marco Mernberger, Thorsten Stiewe, Eli Pikarsky, Moshe Oren, Yinon Ben-Neriah.

Somatic mutations in p53, which inactivate the tumour-suppressor function of p53 and often confer oncogenic gain-of-function properties, are very common in cancer1,2. Here we studied the effects of hotspot gain-of-function mutations in Trp53 (the gene that encodes p53 in mice) in mouse models of WNT-driven intestinal cancer caused by Csnk1a1 deletion3,4 or ApcMin mutation5. Cancer in these models is known to be facilitated by loss of p533,6. We found that mutant versions of p53 had contrasting effects in different segments of the gut: in the distal gut, mutant p53 had the expected oncogenic effect; however, in the proximal gut and in tumour organoids it had a pronounced tumour-suppressive effect. In the tumour-suppressive mode, mutant p53 eliminated dysplasia and tumorigenesis in Csnk1a1-deficient and ApcMin/+ mice, and promoted normal growth and differentiation of tumour organoids derived from these mice. In these settings, mutant p53 was more effective than wild-type p53 at inhibiting tumour formation. Mechanistically, the tumour-suppressive effects of mutant p53 were driven by disruption of the WNT pathway, through preventing the binding of TCF4 to chromatin. Notably, this tumour-suppressive effect was completely abolished by the gut microbiome. Moreover, a single metabolite derived from the gut microbiota-gallic acid-could reproduce the entire effect of the microbiome. Supplementing gut-sterilized p53-mutant mice and p53-mutant organoids with gallic acid reinstated the TCF4-chromatin interaction and the hyperactivation of WNT, thus conferring a malignant phenotype to the organoids and throughout the gut. Our study demonstrates the substantial plasticity of a cancer mutation and highlights the role of the microenvironment in determining its functional outcome.

DOI: https://doi.org/10.1038/s41586-020-2541-0
Autophagy. 2020 Jul 27. 1-2

NPC-phagy: selective autophagy of the nuclear pore complexes.

Zhangyuan Yin, Daniel J Klionsky.

  Selective autophagy is critical for the regulation of cellular homeostasis in organisms from yeast to humans. This process is a specific degradation pathway for a wide variety of substrates including unwanted cytosolic components, such as protein aggregates, damaged and/or superfluous organelles, and pathogens. However, it has been less clear as to whether a protein complex or substructure of an organelle can be targeted for removal by selective autophagy. One example of such a substrate is the nuclear pore complex (NPC), a large macromolecular assembly that is present throughout the nuclear envelope. Here, we highlight two recent studies that demonstrate for the first time that NPCs are targeted for vacuolar degradation through selective autophagy.
ABBREVIATIONS: AIM: Atg8-interacting motif; NE: nuclear envelope; NPC: nuclear pore complex; Nup: nucleoporin; PMN/micronucleophagy: piecemeal microautophagy of the nucleus.

Keywords:  Autophagy; NPC-phagy; Nup159; cargo receptor; nuclear pore complex; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2020.1798199
Nature. 2020 Jul 29.

Mechanisms of stretch-mediated skin expansion at single-cell resolution.

Mariaceleste Aragona, Alejandro Sifrim, Milan Malfait, Yura Song, Jens Van Herck, Sophie Dekoninck, Souhir Gargouri, Gaëlle Lapouge, Benjamin Swedlund, Christine Dubois, Pieter Baatsen, Katlijn Vints, Seungmin Han, Fadel Tissir, Thierry Voet, Benjamin D Simons, Cédric Blanpain.

The ability of the skin to grow in response to stretching has been exploited in reconstructive surgery1. Although the response of epidermal cells to stretching has been studied in vitro2,3, it remains unclear how mechanical forces affect their behaviour in vivo. Here we develop a mouse model in which the consequences of stretching on skin epidermis can be studied at single-cell resolution. Using a multidisciplinary approach that combines clonal analysis with quantitative modelling and single-cell RNA sequencing, we show that stretching induces skin expansion by creating a transient bias in the renewal activity of epidermal stem cells, while a second subpopulation of basal progenitors remains committed to differentiation. Transcriptional and chromatin profiling identifies how cell states and gene-regulatory networks are modulated by stretching. Using pharmacological inhibitors and mouse mutants, we define the step-by-step mechanisms that control stretch-mediated tissue expansion at single-cell resolution in vivo.

DOI: https://doi.org/10.1038/s41586-020-2555-7
Cancer Discov. 2020 Jul 29. pii: CD-19-1274. [Epub ahead of print]

Combined Proteomic and Genetic Interaction Mapping Reveals New RAS Effector Pathways and Susceptibilities.

Marcus Robert Kelly, Kaja Kostyrko, Kyuho Han, Nancie Ann Mooney, Edwin E Jeng, Kaitlyn Spees, Phuong T Dinh, Keene L Abbott, Dana Marie Gwinn, E Alejandro Sweet-Cordero, Michael Cory Bassik, Peter K Jackson.

Activating mutations in RAS GTPases drive many cancers, but limited understanding of less-studied RAS interactors, and of the specific roles of different RAS interactor paralogs, continues to limit target discovery. We developed a multistage discovery and screening process to systematically identify genes conferring RAS-related susceptibilities in lung adenocarcinoma. Using affinity purification mass spectrometry, we generated a protein-protein interaction map of RAS interactors and pathway components containing hundreds of interactions. From this network, we constructed a CRISPR dual knockout library targeting 119 RAS-related genes that we screened for KRAS-dependent genetic interactions (GIs). This approach identified new RAS effectors, including the adhesion controller RADIL and the endocytosis regulator RIN1, and >250 synthetic lethal GIs, including a potent KRAS-dependent interaction between RAP1GDS1 and RHOA. Many GIs link specific paralogs within and between gene families. These findings illustrate the power of multiomic approaches to uncover synthetic lethal combinations specific for hitherto untreatable cancer genotypes.

DOI: https://doi.org/10.1158/2159-8290.CD-19-1274
J Chem Phys. 2020 Jul 21. 153(3): 035105

Molecular dynamics study of lipid bilayers modeling outer and inner leaflets of plasma membranes of mouse hepatocytes. I. Differences in physicochemical properties between the two leaflets.

Yoshimichi Andoh, Shiho Hayakawa, Susumu Okazaki.

Outer and inner leaflets of plasma cell membranes have different lipid compositions, and the membrane properties of each leaflet can differ from each other significantly due to these composition differences. However, because of the experimental difficulty in measuring the membrane properties for each leaflet separately, the differences are not well understood at a molecular level. In this study, we constructed two lipid bilayer systems, modeling outer and inner leaflets of plasma membranes of mouse hepatocytes based on experimental composition data. The ion concentration in the interlamellar water phase was also set to match the concentration in extra- and intracellular fluids. The differences in physical properties between the outer and inner leaflets of mouse hepatocyte cell membrane models were investigated by performing 1.2 μs-long all-atomistic molecular dynamics calculations under physiological temperature and pressure conditions (310.15 K and 1 atm). The calculated electron density profiles along the bilayer normal for each model bilayer system captured well the asymmetric feature of the experimental electron density profile across actual cell plasma membranes, indicating that our procedure of modeling the outer and inner leaflets of the cell plasma membranes was satisfactory. We found that compared to the outer leaflet model, the inner leaflet model had a very bulky and soft structure in the lateral direction. To confirm the differences, membrane fluidity was measured from the lateral diffusivity and relaxation times. The fluidity was significantly higher in the inner leaflet model than in the outer leaflet model. We also discuss two topics that are of wide interest in biology, i.e., the interdigitation of acyl tails of lipid molecules between two monolayers and the lateral concentration fluctuation of lipid molecules in the bilayers.

DOI: https://doi.org/10.1063/5.0012676
Methods Enzymol. 2020 ;pii: S0076-6879(20)30165-8. [Epub ahead of print]641 75-94

IMPACT: Imaging phospholipase d activity with clickable alcohols via transphosphatidylation.

Timothy W Bumpus, Dongjun Liang, Jeremy M Baskin.

  Phospholipase Ds (PLDs) are multifunctional and disease-relevant enzymes operating at the center of phospholipid metabolism and signaling. Physiologically, they hydrolyze abundant phospholipids into phosphatidic acid (PA), a potent lipid second messenger and central biosynthetic intermediate. Given the pleiotropic nature of PA, the multiple locations of PLD activity within single cells, and differences in PLD activities across cell types in vivo, tools with spatiotemporal precision are urgently needed to dissect the signaling functions of PLDs. Here, we describe a toolset for visualizing and quantifying cellular PLD activity with high spatial and temporal resolution. Our approach capitalizes on the ability of PLDs to catalyze transphosphatidylation reactions with exogenous alcohols to generate phosphatidyl alcohols, lipids whose location and abundance report on the extent of PLD-mediated PA synthesis. Our key innovation is to employ functionalized, "clickable," alcohols as PLD substrates, which enables subsequent tagging of the resultant phosphatidyl alcohols with fluorophores or other functional probes for detection via highly selective click chemistry reactions. In this chapter, we describe this method, termed IMPACT (Imaging PLD Activity with Clickable Alcohols via Transphosphatidylation), which can be coupled to downstream analysis by fluorescence microscopy, flow cytometry, HPLC, or mass spectrometry. We describe two variants of IMPACT, one with greater sensitivity, for detecting PLD activity at single-cell and population levels, and one with greater spatiotemporal resolution ("real-time," or RT-IMPACT), for accurately visualizing PLD activity at the subcellular, individual-organelle level. Together, IMPACT represents a major advance in our ability to dissect PLD-mediated PA signaling in native biological settings.

Keywords:  Click chemistry; Imaging; Lipid signaling; Phosphatidic acid; Phospholipase d; Phospholipids; Transphosphatidylation

DOI:  https://doi.org/10.1016/bs.mie.2020.04.037
Diagn Pathol. 2020 Jul 28. 15(1): 100

Deep learning-based image analysis methods for brightfield-acquired multiplex immunohistochemistry images.

Danielle J Fassler, Shahira Abousamra, Rajarsi Gupta, Chao Chen, Maozheng Zhao, David Paredes, Syeda Areeha Batool, Beatrice S Knudsen, Luisa Escobar-Hoyos, Kenneth R Shroyer, Dimitris Samaras, Tahsin Kurc, Joel Saltz.

   BACKGROUND: Multiplex immunohistochemistry (mIHC) permits the labeling of six or more distinct cell types within a single histologic tissue section. The classification of each cell type requires detection of the unique colored chromogens localized to cells expressing biomarkers of interest. The most comprehensive and reproducible method to evaluate such slides is to employ digital pathology and image analysis pipelines to whole-slide images (WSIs). Our suite of deep learning tools quantitatively evaluates the expression of six biomarkers in mIHC WSIs. These methods address the current lack of readily available methods to evaluate more than four biomarkers and circumvent the need for specialized instrumentation to spectrally separate different colors. The use case application for our methods is a study that investigates tumor immune interactions in pancreatic ductal adenocarcinoma (PDAC) with a customized mIHC panel.
METHODS: Six different colored chromogens were utilized to label T-cells (CD3, CD4, CD8), B-cells (CD20), macrophages (CD16), and tumor cells (K17) in formalin-fixed paraffin-embedded (FFPE) PDAC tissue sections. We leveraged pathologist annotations to develop complementary deep learning-based methods: (1) ColorAE is a deep autoencoder which segments stained objects based on color; (2) U-Net is a convolutional neural network (CNN) trained to segment cells based on color, texture and shape; and ensemble methods that employ both ColorAE and U-Net, collectively referred to as (3) ColorAE:U-Net. We assessed the performance of our methods using: structural similarity and DICE score to evaluate segmentation results of ColorAE against traditional color deconvolution; F1 score, sensitivity, positive predictive value, and DICE score to evaluate the predictions from ColorAE, U-Net, and ColorAE:U-Net ensemble methods against pathologist-generated ground truth. We then used prediction results for spatial analysis (nearest neighbor).
RESULTS: We observed that (1) the performance of ColorAE is comparable to traditional color deconvolution for single-stain IHC images (note: traditional color deconvolution cannot be used for mIHC); (2) ColorAE and U-Net are complementary methods that detect 6 different classes of cells with comparable performance; (3) combinations of ColorAE and U-Net into ensemble methods outperform using either ColorAE and U-Net alone; and (4) ColorAE:U-Net ensemble methods can be employed for detailed analysis of the tumor microenvironment (TME). We developed a suite of scalable deep learning methods to analyze 6 distinctly labeled cell populations in mIHC WSIs. We evaluated our methods and found that they reliably detected and classified cells in the PDAC tumor microenvironment. We also present a use case, wherein we apply the ColorAE:U-Net ensemble method across 3 mIHC WSIs and use the predictions to quantify all stained cell populations and perform nearest neighbor spatial analysis. Thus, we provide proof of concept that these methods can be employed to quantitatively describe the spatial distribution immune cells within the tumor microenvironment. These complementary deep learning methods are readily deployable for use in clinical research studies.

Keywords:  Deep learning; Digital pathology image analysis; Multiplex immunohistochemistry; Tumor immune microenvironment

DOI:  https://doi.org/10.1186/s13000-020-01003-0
J Biol Chem. 2020 Jul 30. pii: jbc.RA120.013897. [Epub ahead of print]

The insufficiency of ATG4A in macroautophagy.

Nathan Nguyen, Taryn J Olivas, Antonio Mires, Jiaxin Jin, Shenliang Yu, Lin Luan, Shanta Nag, Karlina J Kauffman, Thomas J Melia.

  During autophagy, LC3 and GABARAP proteins become covalently attached to phosphatidylethanolamine (PE) on the growing autophagosome. This attachment is also reversible. Deconjugation (or delipidation) involves the proteolytic cleavage of an isopeptide bond between LC3 or GABARAP and the PE headgroup. This cleavage is carried about by the ATG4 family of proteases (ATG4A, B, C and D). Many studies have established that ATG4B is the most active of these proteases and is sufficient for autophagy progression in simple cells. Here we examine the second most active protease, ATG4A, to map out key regulatory motifs on the protein and to establish its activity in cells. We utilize fully in vitroreconstitution systems where we control the attachment of LC3/GABARAP members and discover a role for a carboxy-terminal (COOH-terminal) LC3-interacting region (LIR) on ATG4A in regulating its access to LC3/GABARAP. We then use a gene-edited cell line in which all four ATG4 proteases have been knocked out to establish that ATG4A is insufficient to support autophagy and is unable to support GABARAP proteins removal from the membrane. As a result, GABARAP proteins accumulate on membranes other than mature autophagosomes. These results suggest that to support efficient production and consumption of autophagosomes, additional factors are essential including possibly ATG4B itself, or one of its proteolytic products in the LC3 family.

Keywords:  GABARAP Like-1; LC3 Interacting Region (LIR); MST4; autophagy; autophagy-related protein 4A (ATG4); cell biology; delipidation; liposome; membrane reconstitution; phosphorylation

DOI:  https://doi.org/10.1074/jbc.RA120.013897
Am J Physiol Cell Physiol. 2020 Jul 29.

More than just a garbage can: emerging roles of the lysosome as an anabolic organelle in skeletal muscle.

Sidney Abou Sawan, Michael Mazzulla, Daniel R Moore, Nathan Hodson.

  Skeletal muscle is a highly plastic tissue capable of remodeling in response to a range of physiological stimuli including nutrients and exercise. Historically, the lysosome has been considered an essentially catabolic organelle contributing to autophagy, phagocytosis, and exo/endocytosis in skeletal muscle. However, recent evidence has emerged of several anabolic roles for the lysosome including the requirement for autophagy in skeletal muscle mass maintenance, the discovery of the lysosome as an intracellular signaling hub for mTORC1 activation, and the importance of TFEB/lysosomal biogenesis-related signaling in the regulation of mTORC1-mediated protein synthesis. We therefore propose that the lysosome is an understudied organelle with the potential to underpin the skeletal muscle adaptive response to anabolic stimuli. Within this review we describe the molecular regulation of lysosome biogenesis and detail the emerging anabolic roles of the lysosome in skeletal muscle with particular emphasis on how these roles may mediate adaptations to chronic resistance exercise. Furthermore, given the well-established role of amino acids to support muscle protein remodeling, we describe how dietary proteins 'labeled' with stable isotopes could provide a complimentary research tool to better understand how lysosomal biogenesis, autophagy regulation, and/or mTORC1-lysosomal repositioning can mediate the intracellular usage of dietary amino acids in response anabolic stimuli. Finally, we provide avenues for future research with the aim of elucidating how the regulation of this important organelle could mediate skeletal muscle anabolism.

Keywords:  Lysosomal Biogenesis; Lysosome; Resistance Exercise; TFEB; mTORC1

DOI:  https://doi.org/10.1152/ajpcell.00241.2020
Adv Cancer Res. 2020 ;pii: S0065-230X(20)30012-9. [Epub ahead of print]148 147-169

Cyclin D-CDK4/6 functions in cancer.

Xueliang Gao, Gustavo W Leone, Haizhen Wang.

  The mammalian cell cycle is driven by a complex of cyclins and their associated cyclin-dependent kinases (CDKs). Abnormal dysregulation of cyclin-CDK is a hallmark of cancer. D-type cyclins and their associated CDKs (CDK4 and CDK6) are key components of cell cycle machinery in driving G1 to S phase transition via phosphorylating and inactivating the retinoblastoma protein (RB). A body of evidence shows that the cyclin Ds-CDKs axis plays a critical role in cancer through various aspects, such as control of proliferation, senescence, migration, apoptosis, and angiogenesis. CDK4/6 dual-inhibitors show significant efficacy in pre-clinical or clinical cancer therapies either as single agents or in combination with hormone, chemotherapy, irradiation or immune treatments. Of note, as the associated partner of D-type cyclins, CDK6 shows multiple distinct functions from CDK4 in cancer. Depletion of the individual CDK may provide a therapeutic strategy for patients with cancer.

Keywords:  Abemaciclib; CDK4; CDK4/6 inhibitor; CDK6; Cyclin; Cyclin-dependent kinases; PROTAC; Palbociclib; RB; Ribociclib

DOI:  https://doi.org/10.1016/bs.acr.2020.02.002
J Vis Exp. 2020 Jun 30.

A Cost Effective and Adaptable Scratch Migration Assay.

Stephanie D Burr, James A Stewart.

Cell migration is a key component in both physiological and pathological events. Normal cell migration is required for essential functions such as development and mounting an immune response. When a defect or alteration occurs with the cell migration process, it can have detrimental outcomes (i.e., cancer metastasis, wound healing, and scar formation). Due to the importance of cell migration, it is necessary to have access to a cell migration assay that is affordable, adaptable, and repeatable. Utilizing the common scratch migration assay, we have developed a new approach to analyzing cell migration that uses general laboratory equipment. The method described uses visual markers that allow for recapturing specific areas of interest without the use of time-lapse microscopy. In addition, it provides flexibility in the experimental design, ranging from altering the migration matrix substrate to the addition of pharmacological modifiers. Furthermore, this protocol outlines a way to account for the area of cell migration, which is not considered by several methods when examining cell migration. This new approach offers a scratch migration assay to a larger audience and will provide greater opportunity for researchers to examine the physiological and pathophysiological impact of cell migration.

DOI: https://doi.org/10.3791/61527
Biophys J. 2020 Jul 10. pii: S0006-3495(20)30526-9. [Epub ahead of print]

Induction of Ordered Lipid Raft Domain Formation by Loss of Lipid Asymmetry.

Johnna Wellman St Clair, Shinako Kakuda, Erwin London.

How lipid asymmetry impacts ordered lipid domain (raft) formation may yield important clues to how ordered domain formation is regulated in vivo. Under some conditions, a sphingomyelin (SM) and cholesterol-rich ordered domain in one leaflet induces ordered domain formation in the corresponding region of an opposite leaflet composed of unsaturated phosphatidylcholine (PC) and cholesterol. In other conditions, the formation of ordered domains in a SM and cholesterol-rich leaflet can be suppressed by an opposite leaflet containing unsaturated PC and cholesterol. To explore how PC unsaturation influences the balance between these behaviors, domain formation was studied in asymmetric and symmetric lipid vesicles composed of egg SM, cholesterol, and either unsaturated dioleoyl PC (DOPC) or 1-palmitoyl 2-oleoyl PC (POPC). The temperature dependence of ordered domain formation was measured using Förster resonance energy transfer, which detects nanodomains as well as large domains. In cholesterol-containing asymmetric SM+PC outside/PC inside vesicles, the PC-containing inner leaflet tended to destabilize ordered domain formation in the SM+PC-containing outer leaflet relative to ordered domain stability in cholesterol-containing symmetric SM/PC vesicles. Residual ordered domain formation was detected in cholesterol-containing asymmetric SM+DOPC outside/DOPC inside vesicles, but ordered domain formation was completely or almost completely suppressed by asymmetry in cholesterol-containing SM+POPC outside/POPC inside vesicles over the entire temperature range measured. Suppression of ordered domain formation in the latter vesicles was confirmed by fluorescence anisotropy measurements. Because mixtures of SM, POPC, and cholesterol form domains in symmetric vesicles, and this lipid composition mimics plasma membranes to a significant degree, it is possible that under some conditions in vivo the loss of lipid asymmetry could trigger ordered domain formation.

DOI: https://doi.org/10.1016/j.bpj.2020.06.030
Biochim Biophys Acta Mol Cell Res. 2020 Jul 23. pii: S0167-4889(20)30158-0. [Epub ahead of print] 118800

Maintaining social contacts: The physiological relevance of organelle interactions.

Beatriz S C Silva, Laura DiGiovanni, Rechal Kumar, Ruth E Carmichael, Peter K Kim, Michael Schrader.

  Membrane-bound organelles in eukaryotic cells form an interactive network to coordinate and facilitate cellular functions. The formation of close contacts, termed "membrane contact sites" (MCSs), represents an intriguing strategy for organelle interaction and coordinated interplay. Emerging research is rapidly revealing new details of MCSs. They represent ubiquitous and diverse structures, which are important for many aspects of cell physiology and homeostasis. Here, we provide a comprehensive overview of the physiological relevance of organelle contacts. We focus on mitochondria, peroxisomes, the Golgi complex and the plasma membrane, and discuss the most recent findings on their interactions with other subcellular organelles and their multiple functions, including membrane contacts with the ER, lipid droplets and the endosomal/lysosomal compartment.

Keywords:  Acyl-CoA binding domain containing protein; FFAT motif; lipid metabolism; membrane contact sites; mitochondria; peroxisomes

DOI:  https://doi.org/10.1016/j.bbamcr.2020.118800
Proc Natl Acad Sci U S A. 2020 Jul 31. pii: 202008021. [Epub ahead of print]

Lysosomal activity regulates Caenorhabditis elegans mitochondrial dynamics through vitamin B12 metabolism.

Wei Wei, Gary Ruvkun.

  Mitochondrial fission and fusion are highly regulated by energy demand and physiological conditions to control the production, activity, and movement of these organelles. Mitochondria are arrayed in a periodic pattern in Caenorhabditis elegans muscle, but this pattern is disrupted by mutations in the mitochondrial fission component dynamin DRP-1. Here we show that the dramatically disorganized mitochondria caused by a mitochondrial fission-defective dynamin mutation is strongly suppressed to a more periodic pattern by a second mutation in lysosomal biogenesis or acidification. Vitamin B12 is normally imported from the bacterial diet via lysosomal degradation of B12-binding proteins and transport of vitamin B12 to the mitochondrion and cytoplasm. We show that the lysosomal dysfunction induced by gene inactivations of lysosomal biogenesis or acidification factors causes vitamin B12 deficiency. Growth of the C. elegans dynamin mutant on an Escherichia coli strain with low vitamin B12 also strongly suppressed the mitochondrial fission defect. Of the two C. elegans enzymes that require B12, gene inactivation of methionine synthase suppressed the mitochondrial fission defect of a dynamin mutation. We show that lysosomal dysfunction induced mitochondrial biogenesis, which is mediated by vitamin B12 deficiency and methionine restriction. S-adenosylmethionine, the methyl donor of many methylation reactions, including histones, is synthesized from methionine by S-adenosylmethionine synthase; inactivation of the sams-1 S-adenosylmethionine synthase also suppresses the drp-1 fission defect, suggesting that vitamin B12 regulates mitochondrial biogenesis and then affects mitochondrial fission via chromatin pathways.

Keywords:  interorganelle communication; methionine restriction; mitochondrial dynamics; vacuolar V-ATPase; vitamin B12

DOI:  https://doi.org/10.1073/pnas.2008021117
Clin Transl Sci. 2020 Aug 01.

A Phase I Study of Dinaciclib in Combination With MK-2206 in Patients With Advanced Pancreatic Cancer.

ETCTN-9231 Study Team

The combination of drugs targeting Ral and PI3K/AKT signaling has antitumor efficacy in preclinical models of pancreatic cancer. We combined dinaciclib (small molecule cyclin dependent kinase inhibitor with MK-2206 (Akt inhibitor) in patients with previously treated/metastatic pancreatic cancer. Patients were treated with dinaciclib (6-12 mg/m2 i.v.) and MK-2206 (60-135 mg p.o.) weekly. Tumor biopsies were performed to measure pAKT, pERK, and Ki67 at baseline and after one completed cycle (dose level 2 and beyond). Thirty-nine patients participated in the study. The maximum tolerated doses were dinaciclib 9 mg/m2 and MK-2206 135 mg. Treatment-related grade 3 and 4 toxicities included neutropenia, lymphopenia, anemia, hyperglycemia, hyponatremia, and leukopenia. No objectives responses were observed. Four patients (10%) had stable disease as their best response. At the recommended dose, median survival was 2.2 months. Survival rates at 6 and 12 months were 11% and 5%, respectively. There was a nonsignificant reduction in pAKT composite scores between pretreatment and post-treatment biopsies (mean 0.76 vs. 0.63; P = 0.635). The combination of dinaciclib and MK-2206 was a safe regimen in patients with metastatic pancreatic cancer, although without clinical benefit, possibly due to not attaining biologically effective doses. Given the strong preclinical evidence of Ral and AKT inhibition, further studies with better tolerated agents should be considered.

DOI: https://doi.org/10.1111/cts.12802
Molecules. 2020 Jul 28. pii: E3424. [Epub ahead of print]25(15):

The Secret Lives of Fluorescent Membrane Probes as Revealed by Molecular Dynamics Simulations.

Hugo A L Filipe, Maria João Moreno, Luís M S Loura.

  Fluorescent probes have been employed for more than half a century to study the structure and dynamics of model and biological membranes, using spectroscopic and/or microscopic experimental approaches. While their utilization has led to tremendous progress in our knowledge of membrane biophysics and physiology, in some respects the behavior of bilayer-inserted membrane probes has long remained inscrutable. The location, orientation and interaction of fluorophores with lipid and/or water molecules are often not well known, and they are crucial for understanding what the probe is actually reporting. Moreover, because the probe is an extraneous inclusion, it may perturb the properties of the host membrane system, altering the very properties it is supposed to measure. For these reasons, the need for independent methodologies to assess the behavior of bilayer-inserted fluorescence probes has been recognized for a long time. Because of recent improvements in computational tools, molecular dynamics (MD) simulations have become a popular means of obtaining this important information. The present review addresses MD studies of all major classes of fluorescent membrane probes, focusing in the period between 2011 and 2020, during which such work has undergone a dramatic surge in both the number of studies and the variety of probes and properties accessed.

Keywords:  fluorescence; lipid bilayer; membrane probes; molecular dynamics; molecular simulation

DOI:  https://doi.org/10.3390/molecules25153424
J Bioenerg Biomembr. 2020 Jul 26.

Lipid composition of the cancer cell membrane.

Wojciech Szlasa, Iga Zendran, Aleksandra Zalesińska, Mounir Tarek, Julita Kulbacka.

  Cancer cell possesses numerous adaptations to resist the immune system response and chemotherapy. One of the most significant properties of the neoplastic cells is the altered lipid metabolism, and consequently, the abnormal cell membrane composition. Like in the case of phosphatidylcholine, these changes result in the modulation of certain enzymes and accumulation of energetic material, which could be used for a higher proliferation rate. The changes are so prominent, that some lipids, such as phosphatidylserines, could even be considered as the cancer biomarkers. Additionally, some changes of biophysical properties of cell membranes lead to the higher resistance to chemotherapy, and finally to the disturbances in signalling pathways. Namely, the increased levels of certain lipids, like for instance phosphatidylserine, lead to the attenuation of the immune system response. Also, changes in lipid saturation prevent the cells from demanding conditions of the microenvironment. Particularly interesting is the significance of cell membrane cholesterol content in the modulation of metastasis. This review paper discusses the roles of each lipid type in cancer physiology. The review combined theoretical data with clinical studies to show novel therapeutic options concerning the modulation of cell membranes in oncology.

Keywords:  Cancer cells; Lipid membrane; Membrane composition

DOI:  https://doi.org/10.1007/s10863-020-09846-4
Bioinformatics. 2020 Jul 27. pii: btaa688. [Epub ahead of print]

DysRegSig: an R package for identifying gene dysregulations and building mechanistic signatures in cancer.

Quanxue Li, Wentao Dai, Jixiang Liu, Qingqing Sang, Yi-Xue Li, Yuan-Yuan Li.

SUMMARY: Dysfunctional regulations of gene expression programs relevant to fundamental cell processes can drive carcinogenesis. Therefore, systematically identifying dysregulation events is an effective path for understanding carcinogenesis and provides insightful clues to build predictive signatures with mechanistic interpretability for cancer precision medicine. Here, we implemented a machine learning-based gene dysregulation analysis framework in an R package, DysRegSig, which is capable of exploring gene dysregulations from high-dimensional data and building mechanistic signature based on gene dysregulations. DysRegSig can serve as an easy-to-use tool to facilitate gene dysregulation analysis and follow-up analysis.
AVAILABILITY AND IMPLEMENTATION: The source code and user's guide of DysRegSig are freely available at Github: https://github.com/SCBIT-YYLab/DysRegSig.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

DOI: https://doi.org/10.1093/bioinformatics/btaa688