bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2021–05–30
thirty-one papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility.
  2. SAMM50 acts with p62 in piecemeal basal- and OXPHOS-induced mitophagy of SAM and MICOS components.
  3. Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component.
  4. Autophagy in metabolism and quality control: opposing, complementary or interlinked functions?
  5. Restoration of energy homeostasis by SIRT6 extends healthy lifespan.
  6. Mitohormesis reprogrammes macrophage metabolism to enforce tolerance.
  7. A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and pancreatic ductal adenocarcinoma.
  8. Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer.
  9. High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate the progression of pancreatic cancer.
  10. Systemic metastasis-targeted nanotherapeutic reinforces tumor surgical resection and chemotherapy.
  11. Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response.
  12. Small molecule probes for targeting autophagy.
  13. Energy metabolism in brown adipose tissue.
  14. Co-occurrence and mutual exclusivity: what cross-cancer mutation patterns can tell us.
  15. Mitochondrial DNA variation and cancer.
  16. Single-cell RNA sequencing in pancreatic cancer.
  17. Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage.
  18. Dysregulation of PI3K and hippo signaling pathways synergistically induces chronic pancreatitis via Ctgf upregulation.
  19. Chemical tools for dissecting cell division.
  20. Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress.
  21. Targeting ferroptosis in pancreatic cancer: a double-edged sword.
  22. Mitocytosis, a migrasome-mediated mitochondrial quality-control process.
  23. The many faces of cancer evolution.
  24. BAR-Seq clonal tracking of gene-edited cells.
  25. Fibroblasts as confederates of the immune system.
  26. Cell size homeostasis is maintained by CDK4-dependent activation of p38 MAPK.
  27. Strategies for monitoring cell-cell interactions.
  28. 14C-Tracing of Lipid Metabolism.
  29. Aging as a consequence of selection to reduce the environmental risk of dying.
  30. The role of FDG PET/CT or PET/MRI in assessing response to neoadjuvant therapy for patients with borderline or resectable pancreatic cancer: a systematic literature review.
  31. Using redox-sensitive fluorescent probes to record real-time reactive oxygen species production in cells from mouse carotid body slices.
  1. Nat Commun. 2021 May 24. 12(1): 3044
    Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility.
    S Dhara, S Chhangawala, H Chintalapudi, G Askan, V Aveson, A L Massa, L Zhang, D Torres, A P Makohon-Moore, N Lecomte, J P Melchor, J Bermeo, A Cardenas, S Sinha, D Glassman, R Nicolle, R Moffitt, K H Yu, S Leppanen, S Laderman, B Curry, J Gui, V P Balachandran, C Iacobuzio-Donahue, R Chandwani, C S Leslie, S D Leach.
      Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed "ATAC-array", an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.
    DOI:  https://doi.org/10.1038/s41467-021-23237-2
  2. J Cell Biol. 2021 Aug 02. pii: e202009092. [Epub ahead of print]220(8):
    SAMM50 acts with p62 in piecemeal basal- and OXPHOS-induced mitophagy of SAM and MICOS components.
    Yakubu Princely Abudu, Birendra Kumar Shrestha, Wenxin Zhang, Anthimi Palara, Hanne Britt Brenne, Kenneth Bowitz Larsen, Deanna Lynn Wolfson, Gianina Dumitriu, Cristina Ionica Øie, Balpreet Singh Ahluwalia, Gahl Levy, Christian Behrends, Sharon A Tooze, Stephane Mouilleron, Trond Lamark, Terje Johansen.
      Mitophagy is the degradation of surplus or damaged mitochondria by autophagy. In addition to programmed and stress-induced mitophagy, basal mitophagy processes exert organelle quality control. Here, we show that the sorting and assembly machinery (SAM) complex protein SAMM50 interacts directly with ATG8 family proteins and p62/SQSTM1 to act as a receptor for a basal mitophagy of components of the SAM and mitochondrial contact site and cristae organizing system (MICOS) complexes. SAMM50 regulates mitochondrial architecture by controlling formation and assembly of the MICOS complex decisive for normal cristae morphology and exerts quality control of MICOS components. To this end, SAMM50 recruits ATG8 family proteins through a canonical LIR motif and interacts with p62/SQSTM1 to mediate basal mitophagy of SAM and MICOS components. Upon metabolic switch to oxidative phosphorylation, SAMM50 and p62 cooperate to mediate efficient mitophagy.
    DOI:  https://doi.org/10.1083/jcb.202009092
  3. EMBO Mol Med. 2021 May 25. e13502
    Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component.
    Benoit Thibault, Fernanda Ramos-Delgado, Elvire Pons-Tostivint, Nicole Therville, Celia Cintas, Silvia Arcucci, Stephanie Cassant-Sourdy, Gabriela Reyes-Castellanos, Marie Tosolini, Amelie V Villard, Coralie Cayron, Romain Baer, Justine Bertrand-Michel, Delphine Pagan, Dina Ferreira Da Mota, Hongkai Yan, Chiara Falcomatà, Fabrice Muscari, Barbara Bournet, Jean-Pierre Delord, Ezra Aksoy, Alice Carrier, Pierre Cordelier, Dieter Saur, Celine Basset, Julie Guillermet-Guibert.
      Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro-metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We searched for a gene signature that discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. An unbiased approach identified, amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Kα activation signature as predictive of PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3Kα-selective inhibition prevented macro-metastatic evolution by hindering tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Kα inhibition altered the quantity and the species composition of the produced lipid second messenger PIP3 , with a selective decrease of C36:2 PI-3,4,5-P3 . Tumoural PI3Kα inactivation prevented the accumulation of pro-tumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour cell-intrinsic PI3Kα promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution.
    Keywords:  PI3K isoforms; pancreatic cancer; phosphoinositide; targeted therapy; tumour-stroma dialog
    DOI:  https://doi.org/10.15252/emmm.202013502
  4. Autophagy. 2021 May 26.
    Autophagy in metabolism and quality control: opposing, complementary or interlinked functions?
    Vojo Deretic, Guido Kroemer.
      The sensu stricto autophagy, macroautophagy, is considered to be both a metabolic process as well as a bona fide quality control process. The question as to how these two aspects of autophagy are coordinated and whether and why they overlap has implications for fundamental aspects, pathophysiological effects, and pharmacological manipulation of autophagy. At the top of the regulatory cascade controlling autophagy are master regulators of cellular metabolism, such as MTOR and AMPK, which render the system responsive to amino acid and glucose starvation. At the other end exists a variety of specific autophagy receptors, engaged in the selective removal of a diverse array of intracellular targets, from protein aggregates/condensates to whole organelles such as mitochondria, ER, peroxisomes, lysosomes and lipid droplets. Are the roles of autophagy in metabolism and quality control mutually exclusive, independent or interlocked? How are priorities established? What are the molecular links between both phenomena? This article will provide a starting point to formulate these questions, the responses to which should be taken into consideration in future autophagy-based interventions.
    Keywords:  AMPK; ATG; Aging; Akt; Alzheimer’s disease; ESCRT; FOXO; LC3; MTOR; NAD; NASH; Obesity; Parkinson’s Disease; RagA/B; SIRT1; SIRT3; Selective autophagy; TBK1; TCA; TFEB; Tor; acetyl CoA; autophagy; calcienurin; cancer; cardiovascular; diabetes; endoplasmic reticulum; fatty acids; ferritin; galectin; glycogen; glycolysis; heart; immunity; infection; insulin; lipid droplets; liver; lysosomes; metabolism; mitochondria; mitophagy; neurodegeneration; nutrition; oxidative phosphorylation; p62 SQSTM1; peroxisome; quality control; sirtuin
    DOI:  https://doi.org/10.1080/15548627.2021.1933742
  5. Nat Commun. 2021 May 28. 12(1): 3208
    Restoration of energy homeostasis by SIRT6 extends healthy lifespan.
    A Roichman, S Elhanati, M A Aon, I Abramovich, A Di Francesco, Y Shahar, M Y Avivi, M Shurgi, A Rubinstein, Y Wiesner, A Shuchami, Z Petrover, I Lebenthal-Loinger, O Yaron, A Lyashkov, C Ubaida-Mohien, Y Kanfi, B Lerrer, P J Fernández-Marcos, M Serrano, E Gottlieb, R de Cabo, H Y Cohen.
      Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD+-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.
    DOI:  https://doi.org/10.1038/s41467-021-23545-7
  6. Nat Metab. 2021 May;3(5): 618-635
    Mitohormesis reprogrammes macrophage metabolism to enforce tolerance.
    Greg A Timblin, Kevin M Tharp, Breanna Ford, Janet M Winchester, Jerome Wang, Stella Zhu, Rida I Khan, Shannon K Louie, Anthony T Iavarone, Johanna Ten Hoeve, Daniel K Nomura, Andreas Stahl, Kaoru Saijo.
      Macrophages generate mitochondrial reactive oxygen species and mitochondrial reactive electrophilic species as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically driven and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state wherein stimulus-induced pro-inflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyoestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and pro-inflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mitochondrial reactive oxygen species and mitochondrial reactive electrophilic species are TLR-dependent signalling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signalling and pharmacologically triggering mitohormesis represents a new anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of pro-inflammatory gene transcription by mitochondria.
    DOI:  https://doi.org/10.1038/s42255-021-00392-w
  7. Cancer Res. 2021 May 28. pii: canres.0427.2021. [Epub ahead of print]
    A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and pancreatic ductal adenocarcinoma.
    Vishaka Gopalan, Arashdeep Singh, Farid Rashidi Mehrabadi, Li Wang, Eytan Ruppin, H Efsun Arda, Sridhar Hannenhalli.
      Pancreatic ductal adenocarcinoma (PDAC) can originate either from acinar or ductal cells in the adult pancreas. In this study, we re-analyzed multiple pancreas and PDAC single-cell RNA-seq datasets and found a subset of non-malignant acinar cells, which we refer to as acinar edge (AE) cells, whose transcriptomes highly diverge from a typical acinar cell in each dataset. Genes upregulated among AE cells were enriched for transcriptomic signatures of pancreatic progenitors, acinar dedifferentiation, and several oncogenic programs. AE-upregulated genes were upregulated in human PDAC tumors, and consistently, their promoters were hypomethylated. High expression of these genes was associated with poor patient survival. The fraction of AE-like cells increased with age in healthy pancreatic tissue, which was not explained by clonal mutations, thus pointing to a non-genetic source of variation. The fraction of AE-like cells was also significantly higher in human pancreatitis samples. Finally, cells with edge-like states were observed in lung, liver, prostate, and colon tissues, suggesting that sub-populations of healthy cells across tissues can exist in pre-neoplastic states.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0427
  8. Nat Commun. 2021 May 27. 12(1): 3199
    Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer.
    Bernard Pereira, Christopher T Chen, Lipika Goyal, Charlotte Walmsley, Christopher J Pinto, Islam Baiev, Read Allen, Laura Henderson, Supriya Saha, Stephanie Reyes, Martin S Taylor, Donna M Fitzgerald, Maida Williams Broudo, Avinash Sahu, Xin Gao, Wendy Winckler, A Rose Brannon, Jeffrey A Engelman, Rebecca Leary, James R Stone, Catarina D Campbell, Dejan Juric.
      In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.
    DOI:  https://doi.org/10.1038/s41467-021-23394-4
  9. Cancer Lett. 2021 May 24. pii: S0304-3835(21)00226-3. [Epub ahead of print]
    High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate the progression of pancreatic cancer.
    Anthony Lin, Jennifer Feng, Xiang Chen, Dunrui Wang, Megan Wong, George Zhang, Joseph Na, Tiantian Zhang, Zhengming Chen, Yao-Tseng Chen, Yi-Chieh Nancy Du.
      Pancreatic cancer has the lowest survival rate in all types of cancer. Pancreatic cancer patients are often diagnosed at advanced stages. A better therapeutic development for this devastating disease is urgently needed. Receptor for hyaluronan-mediated motility (RHAMM), not expressed in adult normal pancreas, has been suggested as a prognostic factor and a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET). In this study, we initially sought to determine whether genetic deletion of RHAMM would slow down pancreatic cancer progression using Rhamm-/- mice. However, we found that Rhamm-/- mice expressed a truncated HMMRΔexon8-16 protein at higher abundance levels than wild-type RHAMM. While HMMRΔexon8-16 did not enable malignant progression of pancreatic intraepithelial neoplasia in p48-Cre; LSL-KRASG12D mice, it accelerated the formation of invasive PDAC and shortened the survival of p48-Cre; LSL-KRASG12D mice with heterozygous p53 knockout. KrasG12D PDAC mice with homozygous p53 knockout mice died around 10 weeks, and the effect of HMMRΔexon8-16 was not apparent in these mice with short life span. In addition, HMMRΔexon8-16 shortened the survival of PNET-bearing RIP-Tag mice, which had inactivated p53. In our analysis of TCGA dataset, pancreatic cancer patients with mutant TP53 or loss of one copy of TP53 had higher RHAMM expression, which, combined, predicted worse outcomes. Taken together, by collaborating with dysfunctional p53, high levels of HMMRΔexon8-16 that lacks the centrosome targeting domain and degrons for interaction with the Anaphase-Promoting Complex (APC) accelerated pancreatic cancer progression.
    Keywords:  Mouse models; Pancreatic ductal adenocarcinoma; Pancreatic neuroendocrine tumor; RHAMM; p53
    DOI:  https://doi.org/10.1016/j.canlet.2021.05.011
  10. Nat Commun. 2021 May 27. 12(1): 3187
    Systemic metastasis-targeted nanotherapeutic reinforces tumor surgical resection and chemotherapy.
    Minjun Xu, Kaili Hu, Yipu Liu, Yukun Huang, Shanshan Liu, Yu Chen, Dayuan Wang, Songlei Zhou, Qian Zhang, Ni Mei, Huiping Lu, Fengan Li, Xiaoling Gao, Jun Chen.
      Failure of conventional clinical therapies such as tumor resection and chemotherapy are mainly due to the ineffective control of tumor metastasis. Metastasis consists of three steps: (i) tumor cells extravasate from the primary sites into the circulation system via epithelial-mesenchymal transition (EMT), (ii) the circulating tumor cells (CTCs) form "micro-thrombi" with platelets to evade the immune surveillance in circulation, and (iii) the CTCs colonize in the pre-metastatic niche. Here, we design a systemic metastasis-targeted nanotherapeutic (H@CaPP) composed of an anti-inflammatory agent, piceatannol, and an anti-thrombotic agent, low molecular weight heparin, to hinder the multiple steps of tumor metastasis. H@CaPP is found efficiently impeded EMT, inhibited the formation of "micro-thrombi", and prevented the development of pre-metastatic niche. When combined with surgical resection or chemotherapy, H@CaPP efficiently inhibits tumor metastasis and prolonged overall survival of tumor-bearing mice. Collectively, we provide a simple and effective systemic metastasis-targeted nanotherapeutic for combating tumor metastasis.
    DOI:  https://doi.org/10.1038/s41467-021-23466-5
  11. Cell Discov. 2021 May 25. 7(1): 36
    Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response.
    Yu Wang, Yiyi Liang, Haiyan Xu, Xiao Zhang, Tiebo Mao, Jiujie Cui, Jiayu Yao, Yongchao Wang, Feng Jiao, Xiuying Xiao, Jiong Hu, Qing Xia, Xiaofei Zhang, Xujun Wang, Yongwei Sun, Deliang Fu, Lei Shen, Xiaojiang Xu, Jing Xue, Liwei Wang.
      The current pathological and molecular classification of pancreatic ductal adenocarcinoma (PDAC) provides limited guidance for treatment options, especially for immunotherapy. Cancer-associated fibroblasts (CAFs) are major players of desmoplastic stroma in PDAC, modulating tumor progression and therapeutic response. Using single-cell RNA sequencing, we explored the intertumoral heterogeneity among PDAC patients with different degrees of desmoplasia. We found substantial intertumoral heterogeneity in CAFs, ductal cancer cells, and immune cells between the extremely dense and loose types of PDACs (dense-type, high desmoplasia; loose-type, low desmoplasia). Notably, no difference in CAF abundance was detected, but a novel subtype of CAFs with a highly activated metabolic state (meCAFs) was found in loose-type PDAC compared to dense-type PDAC. MeCAFs had highly active glycolysis, whereas the corresponding cancer cells used oxidative phosphorylation as a major metabolic mode rather than glycolysis. We found that the proportion and activity of immune cells were much higher in loose-type PDAC than in dense-type PDAC. Then, the clinical significance of the CAF subtypes was further validated in our PDAC cohort and a public database. PDAC patients with abundant meCAFs had a higher risk of metastasis and a poor prognosis but showed a dramatically better response to immunotherapy (64.71% objective response rate, one complete response). We characterized the intertumoral heterogeneity of cellular components, immune activity, and metabolic status between dense- and loose-type PDACs and identified meCAFs as a novel CAF subtype critical for PDAC progression and the susceptibility to immunotherapy.
    DOI:  https://doi.org/10.1038/s41421-021-00271-4
  12. Nat Chem Biol. 2021 Jun;17(6): 653-664
    Small molecule probes for targeting autophagy.
    Thomas Whitmarsh-Everiss, Luca Laraia.
      Autophagy is implicated in a wide range of (patho)physiological processes including maintenance of cellular homeostasis, neurodegenerative disorders, aging and cancer. As such, small molecule autophagy modulators are in great demand, both for their ability to act as tools to better understand this essential process and as potential therapeutics. Despite substantial advances in the field, major challenges remain in the development and comprehensive characterization of probes that are specific to autophagy. In this Review, we discuss recent developments in autophagy-modulating small molecules, including the specific challenges faced in the development of activators and inhibitors, and recommend guidelines for their use. Finally, we discuss the potential to hijack the process for targeted protein degradation, an area of great importance in chemical biology and drug discovery.
    DOI:  https://doi.org/10.1038/s41589-021-00768-9
  13. FEBS J. 2021 May 24.
    Energy metabolism in brown adipose tissue.
    Zhichao Wang, Qiong A Wang, Yong Liu, Lei Jiang.
      Brown adipose tissue (BAT) is well known to burn calories through uncoupled respiration, producing heat to maintain body temperature. This 'calorie wasting' feature makes BAT a special tissue, which can function as an 'energy sink' in mammals. While a combination of high energy intake and low energy expenditure is the leading cause of overweight and obesity in modern society, activating a safe 'energy sink' has been proposed as a promising obesity treatment strategy. Metabolically, lipids and glucose have been viewed as the major energy substrates in BAT, while succinate, lactate, branched-chain amino acids, and other metabolites can also serve as energy substrates for thermogenesis. Since the cataplerotic and anaplerotic reactions of these metabolites interconnect with each other, BAT relies on its dynamic, flexible, and complex metabolism to support its special function. In this review, we summarize how BAT orchestrates the metabolic utilization of various nutrients to support thermogenesis and contributes to whole-body metabolic homeostasis.
    Keywords:  brown adipose tissue; glucose metabolism; metabolic flux; obesity; thermogenesis
    DOI:  https://doi.org/10.1111/febs.16015
  14. Trends Cancer. 2021 May 21. pii: S2405-8033(21)00101-1. [Epub ahead of print]
    Co-occurrence and mutual exclusivity: what cross-cancer mutation patterns can tell us.
    Geniver El Tekle, Tiziano Bernasocchi, Arun M Unni, Francesco Bertoni, Davide Rossi, Mark A Rubin, Jean-Philippe Theurillat.
      Cancer is the dysregulated proliferation of cells caused by acquired mutations in key driver genes. The most frequently mutated driver genes promote tumorigenesis in various organisms, cell types, and genetic backgrounds. However, recent cancer genomics studies also point to the existence of context-dependent driver gene functions, where specific mutations occur predominately or even exclusively in certain tumor types or genetic backgrounds. Here, we review examples of co-occurring and mutually exclusive driver gene mutation patterns across cancer genomes and discuss their underlying biology. While co-occurring driver genes typically activate collaborating oncogenic pathways, we identify two distinct biological categories of incompatibilities among the mutually exclusive driver genes depending on whether the mutated drivers trigger the same or divergent tumorigenic pathways. Finally, we discuss possible therapeutic avenues emerging from the study of incompatible driver gene mutations.
    Keywords:  cancer driver mutations; co-occurrence; driver genes antagonism; genomic patterns; mutual exclusivity; pathway redundancy and divergence; synergy; synthetic essentiality; synthetic lethality
    DOI:  https://doi.org/10.1016/j.trecan.2021.04.009
  15. Nat Rev Cancer. 2021 May 27.
    Mitochondrial DNA variation and cancer.
    Piotr K Kopinski, Larry N Singh, Shiping Zhang, Marie T Lott, Douglas C Wallace.
      Variation in the mitochondrial DNA (mtDNA) sequence is common in certain tumours. Two classes of cancer mtDNA variants can be identified: de novo mutations that act as 'inducers' of carcinogenesis and functional variants that act as 'adaptors', permitting cancer cells to thrive in different environments. These mtDNA variants have three origins: inherited variants, which run in families, somatic mutations arising within each cell or individual, and variants that are also associated with ancient mtDNA lineages (haplogroups) and are thought to permit adaptation to changing tissue or geographic environments. In addition to mtDNA sequence variation, mtDNA copy number and perhaps transfer of mtDNA sequences into the nucleus can contribute to certain cancers. Strong functional relevance of mtDNA variation has been demonstrated in oncocytoma and prostate cancer, while mtDNA variation has been reported in multiple other cancer types. Alterations in nuclear DNA-encoded mitochondrial genes have confirmed the importance of mitochondrial metabolism in cancer, affecting mitochondrial reactive oxygen species production, redox state and mitochondrial intermediates that act as substrates for chromatin-modifying enzymes. Hence, subtle changes in the mitochondrial genotype can have profound effects on the nucleus, as well as carcinogenesis and cancer progression.
    DOI:  https://doi.org/10.1038/s41568-021-00358-w
  16. Nat Rev Gastroenterol Hepatol. 2021 May 26.
    Single-cell RNA sequencing in pancreatic cancer.
    Jincheng Han, Ronald A DePinho, Anirban Maitra.
      
    DOI:  https://doi.org/10.1038/s41575-021-00471-z
  17. Immunity. 2021 May 19. pii: S1074-7613(21)00187-4. [Epub ahead of print]
    Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage.
    Anna Barkaway, Loïc Rolas, Régis Joulia, Jennifer Bodkin, Tchern Lenn, Charlotte Owen-Woods, Natalia Reglero-Real, Monja Stein, Laura Vázquez-Martínez, Tamara Girbl, Robin N Poston, Matthew Golding, Rebecca S Saleeb, Aude Thiriot, Ulrich H von Andrian, Johan Duchene, Mathieu-Benoit Voisin, Cleo L Bishop, David Voehringer, Axel Roers, Antal Rot, Tim Lämmermann, Sussan Nourshargh.
      Aging is associated with dysregulated immune functions. Here, we investigated the impact of age on neutrophil diapedesis. Using confocal intravital microscopy, we found that in aged mice, neutrophils adhered to vascular endothelium in inflamed tissues but exhibited a high frequency of reverse transendothelial migration (rTEM). This retrograde breaching of the endothelium by neutrophils was governed by enhanced production of the chemokine CXCL1 from mast cells that localized at endothelial cell (EC) junctions. Increased EC expression of the atypical chemokine receptor 1 (ACKR1) supported this pro-inflammatory milieu in aged venules. Accumulation of CXCL1 caused desensitization of the chemokine receptor CXCR2 on neutrophils and loss of neutrophil directional motility within EC junctions. Fluorescent tracking revealed that in aged mice, neutrophils undergoing rTEM re-entered the circulation and disseminated to the lungs where they caused vascular leakage. Thus, neutrophils stemming from a local inflammatory site contribute to remote organ damage, with implication to the dysregulated systemic inflammation associated with aging.
    Keywords:  ACKR1; CXCR2; Neutrophils; aging; chemokines; diapedesis; endothelium; extravasation; inflammation; mast cells
    DOI:  https://doi.org/10.1016/j.immuni.2021.04.025
  18. J Clin Invest. 2021 May 25. pii: 143414. [Epub ahead of print]
    Dysregulation of PI3K and hippo signaling pathways synergistically induces chronic pancreatitis via Ctgf upregulation.
    Takeshi Tamura, Takahiro Kodama, Katsuhiko Sato, Kazuhiro Murai, Teppei Yoshioka, Minoru Shigekawa, Ryoko Yamada, Hayato Hikita, Ryotaro Sakamori, Hirofumi Akita, Hidetoshi Eguchi, Randy L Johnson, Hideki Yokoi, Masashi Mukoyama, Tomohide Tatsumi, Tetsuo Takehara.
      The role of PI3K and Hippo signaling in chronic pancreatitis (CP) pathogenesis is unclear. Therefore, we assessed the involvement of these pathways in CP by examining the PI3K and Hippo signaling components PTEN and SAV1, respectively. We observed significant decreases in pancreatic PTEN and SAV1 levels in 2 murine CP models: repeated caerulein injection and pancreatic ductal ligation. Additionally, pancreas-specific deletion of Pten and Sav1 (DKO) induced CP in mice. Pancreatic connective tissue growth factor (CTGF) was markedly upregulated in both CP models and DKO mice, and pancreatic CCAAT/enhancer-binding protein alpha (CEBPA) expression was downregulated in the CP models. Interestingly, in pancreatic acinar cells (PACs), CEBPA knockdown reduced PTEN and SAV1 and increased CTGF levels in vitro. Furthermore, CEBPA knockdown in PACs induced acinar-to-ductal metaplasia and activation of cocultured macrophages and pancreatic stellate cells. These results were mitigated by CTGF inhibition. CP in DKO mice was also ameliorated by Ctgf gene deletion, and caerulein-induced CP was alleviated by antibody-mediated CTGF neutralization. Finally, we observed significantly decreased PTEN, SAV1, and CEBPA and increased CTGF levels in human CP tissues compared to nonpancreatitis tissues. Taken together, our results indicate that dysregulation of PI3K and Hippo signaling induces CP via CTGF upregulation.
    Keywords:  Gastroenterology; Molecular pathology
    DOI:  https://doi.org/10.1172/JCI143414
  19. Nat Chem Biol. 2021 Jun;17(6): 632-640
    Chemical tools for dissecting cell division.
    Geng-Yuan Chen, Michael A Lampson.
      Components of the cell division machinery typically function at varying cell cycle stages and intracellular locations. To dissect cellular mechanisms during the rapid division process, small-molecule probes act as complementary approaches to genetic manipulations, with advantages of temporal and in some cases spatial control and applicability to multiple model systems. This Review focuses on recent advances in chemical probes and applications to address select questions in cell division. We discuss uses of both enzyme inhibitors and chemical inducers of dimerization, as well as emerging techniques to promote future investigations. Overall, these concepts may open new research directions for applying chemical probes to advance cell biology.
    DOI:  https://doi.org/10.1038/s41589-021-00798-3
  20. Nucleic Acids Res. 2021 May 22. pii: gkab362. [Epub ahead of print]
    Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress.
    Jagannath Misra, Michael J Holmes, Emily T Mirek, Michael Langevin, Hyeong-Geug Kim, Kenneth R Carlson, Malcolm Watford, X Charlie Dong, Tracy G Anthony, Ronald C Wek.
      Appropriate regulation of the Integrated stress response (ISR) and mTORC1 signaling are central for cell adaptation to starvation for amino acids. Halofuginone (HF) is a potent inhibitor of aminoacylation of tRNAPro with broad biomedical applications. Here, we show that in addition to translational control directed by activation of the ISR by general control nonderepressible 2 (GCN2), HF increased free amino acids and directed translation of genes involved in protein biogenesis via sustained mTORC1 signaling. Deletion of GCN2 reduced cell survival to HF whereas pharmacological inhibition of mTORC1 afforded protection. HF treatment of mice synchronously activated the GCN2-mediated ISR and mTORC1 in liver whereas Gcn2-null mice allowed greater mTORC1 activation to HF, resulting in liver steatosis and cell death. We conclude that HF causes an amino acid imbalance that uniquely activates both GCN2 and mTORC1. Loss of GCN2 during HF creates a disconnect between metabolic state and need, triggering proteostasis collapse.
    DOI:  https://doi.org/10.1093/nar/gkab362
  21. Trends Cancer. 2021 May 19. pii: S2405-8033(21)00097-2. [Epub ahead of print]
    Targeting ferroptosis in pancreatic cancer: a double-edged sword.
    Xin Chen, Rui Kang, Guido Kroemer, Daolin Tang.
      Pancreatic ductal adenocarcinoma (PDAC) remains an aggressive malignancy with a 5-year survival rate below 10%. Its unique genetic makeup and tumor microenvironment produce a lack of response to current treatments, including chemotherapy, radiotherapy, and immunotherapy. Recent preclinical studies have revealed that ferroptosis, an iron-dependent form of nonapoptotic cell death driven by unrestricted lipid peroxidation, may be an attractive therapeutic goal in PDAC. Understanding the dual role of ferroptotic cell death in both promoting and suppressing tumor immunity, as well as its integrated regulatory mechanisms and signaling pathways, may lead to more effective treatment designs for clinical trials of PDAC and may minimize or delay the emergence of drug resistance or side effects.
    Keywords:  cell death; ferroptosis; pancreatic cancer; redox signaling; therapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2021.04.005
  22. Cell. 2021 May 27. pii: S0092-8674(21)00530-4. [Epub ahead of print]184(11): 2896-2910.e13
    Mitocytosis, a migrasome-mediated mitochondrial quality-control process.
    Haifeng Jiao, Dong Jiang, Xiaoyu Hu, Wanqing Du, Liangliang Ji, Yuzhuo Yang, Xiaopeng Li, Takami Sho, Xuan Wang, Ying Li, Yu-Ting Wu, Yau-Huei Wei, Xiaoyu Hu, Li Yu.
      Damaged mitochondria need to be cleared to maintain the quality of the mitochondrial pool. Here, we report mitocytosis, a migrasome-mediated mitochondrial quality-control process. We found that, upon exposure to mild mitochondrial stresses, damaged mitochondria are transported into migrasomes and subsequently disposed of from migrating cells. Mechanistically, mitocytosis requires positioning of damaged mitochondria at the cell periphery, which occurs because damaged mitochondria avoid binding to inward motor proteins. Functionally, mitocytosis plays an important role in maintaining mitochondrial quality. Enhanced mitocytosis protects cells from mitochondrial stressor-induced loss of mitochondrial membrane potential (MMP) and mitochondrial respiration; conversely, blocking mitocytosis causes loss of MMP and mitochondrial respiration under normal conditions. Physiologically, we demonstrate that mitocytosis is required for maintaining MMP and viability in neutrophils in vivo. We propose that mitocytosis is an important mitochondrial quality-control process in migrating cells, which couples mitochondrial homeostasis with cell migration.
    Keywords:  migrasome; mitochondrial quality control; mitochondrion; mitocytosis; mitosome
    DOI:  https://doi.org/10.1016/j.cell.2021.04.027
  23. iScience. 2021 May 21. 24(5): 102403
    The many faces of cancer evolution.
    Giovanni Ciriello, Luca Magnani.
      Cancer cells acquire genotypic and phenotypic changes over the course of the disease. A minority of these changes enhance cell fitness, allowing a tumor to evolve and overcome environmental constraints and treatment. Cancer evolution is driven by diverse processes governed by different rules, such as discrete and irreversible genetic variants and continuous and reversible plastic reprogramming. In this perspective, we explore the role of cell plasticity in tumor evolution through specific examples. We discuss epigenetic and transcriptional reprogramming in "disease progression" of solid tumors, through the lens of the epithelial-to-mesenchymal transition, and "treatment resistance", in the context endocrine therapy in hormone-driven cancers. These examples offer a paradigm of the features and challenges of cell plastic evolution, and we investigate how recent technological advances can address these challenges. Cancer evolution is a multi-faceted process, whose understanding and harnessing will require an equally diverse prism of perspectives and approaches.
    Keywords:  Cancer; Evolutionary Biology
    DOI:  https://doi.org/10.1016/j.isci.2021.102403
  24. Nat Protoc. 2021 May 24.
    BAR-Seq clonal tracking of gene-edited cells.
    Samuele Ferrari, Stefano Beretta, Aurelien Jacob, Davide Cittaro, Luisa Albano, Ivan Merelli, Luigi Naldini, Pietro Genovese.
      Gene editing by engineered nucleases has revolutionized the field of gene therapy by enabling targeted and precise modification of the genome. However, the limited availability of methods for clonal tracking of edited cells has resulted in a paucity of information on the diversity, abundance and behavior of engineered clones. Here we detail the wet laboratory and bioinformatic BAR-Seq pipeline, a strategy for clonal tracking of cells harboring homology-directed targeted integration of a barcoding cassette. We present the BAR-Seq web application, an online, freely available and easy-to-use software that allows performing clonal tracking analyses on raw sequencing data without any computational resources or advanced bioinformatic skills. BAR-Seq can be applied to most editing strategies, and we describe its use to investigate the clonal dynamics of human edited hematopoietic stem/progenitor cells in xenotransplanted hosts. Notably, BAR-Seq may be applied in both basic and translational research contexts to investigate the biology of edited cells and stringently compare editing protocols at a clonal level. Our BAR-Seq pipeline allows library preparation and validation in a few days and clonal analyses of edited cell populations in 1 week.
    DOI:  https://doi.org/10.1038/s41596-021-00529-x
  25. Immunol Rev. 2021 May 25.
    Fibroblasts as confederates of the immune system.
    Donovan Correa-Gallegos, Dongsheng Jiang, Yuval Rinkevich.
      Fibroblastic stromal cells are as diverse, in origin and function, as the niches they fashion in the mammalian body. This cellular variety impacts the spectrum of responses elicited by the immune system. Fibroblast influence on the immune system keeps evolving our perspective on fibroblast roles and functions beyond just a passive structural part of organs. This review discusses the foundations of fibroblastic stromal-immune crosstalk, under the scope of stromal heterogeneity as a basis for tissue-specific tutoring of the immune system. Focusing on the skin as a relevant immunological organ, we detail the complex interactions between distinct fibroblast populations and immune cells that occur during homeostasis, injury repair, scarring, and disease. We further review the relevance of fibroblastic stromal cell heterogeneity and how this heterogeneity is central to regulate the immune system from its inception during embryonic development into adulthood.
    Keywords:  development; extracellular matrix; fibroblast; immunological niche; scarring; skin; stromal cell; wound healing
    DOI:  https://doi.org/10.1111/imr.12972
  26. Dev Cell. 2021 May 17. pii: S1534-5807(21)00399-3. [Epub ahead of print]
    Cell size homeostasis is maintained by CDK4-dependent activation of p38 MAPK.
    Ceryl Tan, Miriam B Ginzberg, Rachel Webster, Seshu Iyengar, Shixuan Liu, David Papadopoli, John Concannon, Yuan Wang, Douglas S Auld, Jeremy L Jenkins, Hannes Rost, Ivan Topisirovic, Andreas Hilfinger, W Brent Derry, Nish Patel, Ran Kafri.
      While molecules that promote the growth of animal cells have been identified, it remains unclear how such signals are orchestrated to determine a characteristic target size for different cell types. It is increasingly clear that cell size is determined by size checkpoints-mechanisms that restrict the cell cycle progression of cells that are smaller than their target size. Previously, we described a p38 MAPK-dependent cell size checkpoint mechanism whereby p38 is selectively activated and prevents cell cycle progression in cells that are smaller than a given target size. In this study, we show that the specific target size required for inactivation of p38 and transition through the cell cycle is determined by CDK4 activity. Our data suggest a model whereby p38 and CDK4 cooperate analogously to the function of a thermostat: while p38 senses irregularities in size, CDK4 corresponds to the thermostat dial that sets the target size.
    Keywords:  CDK4; cell growth; cell size; cell size checkpoint; cell size homeostasis; cell size regulation; critical size; cyclin D1; p38 MAPK; target size
    DOI:  https://doi.org/10.1016/j.devcel.2021.04.030
  27. Nat Chem Biol. 2021 Jun;17(6): 641-652
    Strategies for monitoring cell-cell interactions.
    Tyler J Bechtel, Tamara Reyes-Robles, Olugbeminiyi O Fadeyi, Rob C Oslund.
      Multicellular organisms depend on physical cell-cell interactions to control physiological processes such as tissue formation, neurotransmission and immune response. These intercellular binding events can be both highly dynamic in their duration and complex in their composition, involving the participation of many different surface and intracellular biomolecules. Untangling the intricacy of these interactions and the signaling pathways they modulate has greatly improved insight into the biological processes that ensue upon cell-cell engagement and has led to the development of protein- and cell-based therapeutics. The importance of monitoring physical cell-cell interactions has inspired the development of several emerging approaches that effectively interrogate cell-cell interfaces with molecular-level detail. Specifically, the merging of chemistry- and biology-based technologies to deconstruct the complexity of cell-cell interactions has provided new avenues for understanding cell-cell interaction biology and opened opportunities for therapeutic development.
    DOI:  https://doi.org/10.1038/s41589-021-00790-x
  28. Methods Mol Biol. 2021 ;2295 59-80
    14C-Tracing of Lipid Metabolism.
    Hari Kiran Kotapati, Philip D Bates.
      Lipids are produced through a dynamic metabolic network involving branch points, cycles, reversible reactions, parallel reactions in different subcellular compartments, and distinct pools of the same lipid class involved in different parts of the network. For example, diacylglycerol (DAG) is a biosynthetic and catabolic intermediate of many different lipid classes. Triacylglycerol can be synthesized from DAG assembled de novo, or from DAG produced by catabolism of membrane lipids, most commonly phosphatidylcholine. Quantification of lipids provides a snapshot of the lipid abundance at the time they were extracted from the given tissue. However, quantification alone does not provide information on the path of carbon flux through the metabolic network to synthesize each lipid. Understanding lipid metabolic flux requires tracing lipid metabolism with isotopically labeled substrates over time in living tissue. [14C]acetate and [14C]glycerol are commonly utilized substrates to measure the flux of nascent fatty acids and glycerol backbones through the lipid metabolic network in vivo. When combined with mutant or transgenic plants, tracing of lipid metabolism can provide information on the molecular control of lipid metabolic flux. This chapter provides a method for tracing in vivo lipid metabolism in developing Arabidopsis thaliana seeds, including analysis of 14C labeled lipid classes and fatty acid regiochemistry through both thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) approaches.
    Keywords:  Carbon-14; Flow liquid scintillation counting; Metabolic flux; Pulse–chase; Radiolabel
    DOI:  https://doi.org/10.1007/978-1-0716-1362-7_5
  29. Proc Natl Acad Sci U S A. 2021 Jun 01. pii: e2102088118. [Epub ahead of print]118(22):
    Aging as a consequence of selection to reduce the environmental risk of dying.
    Stig W Omholt, Thomas B L Kirkwood.
      Each animal in the Darwinian theater is exposed to a number of abiotic and biotic risk factors causing mortality. Several of these risk factors are intimately associated with the act of energy acquisition as such and with the amount of reserve the organism has available from this acquisition for overcoming temporary distress. Because a considerable fraction of an individual's lifetime energy acquisition is spent on somatic maintenance, there is a close link between energy expenditure on somatic maintenance and mortality risk. Here, we show, by simple life-history theory reasoning backed up by empirical cohort survivorship data, how reduction of mortality risk might be achieved by restraining allocation to somatic maintenance, which enhances lifetime fitness but results in aging. Our results predict the ubiquitous presence of senescent individuals in a highly diverse group of natural animal populations, which may display constant, increasing, or decreasing mortality with age. This suggests that allocation to somatic maintenance is primarily tuned to expected life span by stabilizing selection and is not necessarily traded against reproductive effort or other traits. Due to this ubiquitous strategy of modulating the somatic maintenance budget so as to increase fitness under natural conditions, it follows that individuals kept in protected environments with very low environmental mortality risk will have their expected life span primarily defined by somatic damage accumulation mechanisms laid down by natural selection in the wild.
    Keywords:  aging; evolution; life-history modeling; mortality risk; senescence
    DOI:  https://doi.org/10.1073/pnas.2102088118
  30. Ann Nucl Med. 2021 May 28.
    The role of FDG PET/CT or PET/MRI in assessing response to neoadjuvant therapy for patients with borderline or resectable pancreatic cancer: a systematic literature review.
    Laura Evangelista, Pietro Zucchetta, Lucia Moletta, Simone Serafini, Gianluca Cassarino, Nicola Pegoraro, Francesca Bergamo, Cosimo Sperti, Diego Cecchin.
      The aim of the present systematic review is to examine the role of fluorodeoxyglucose (FDG) positron emission tomography (PET) associated with computed tomography (CT) or magnetic resonance imaging (MRI) in assessing response to preoperative chemotherapy or chemoradiotherapy (CRT) for patients with borderline and resectable pancreatic ductal adenocarcinoma (PDAC). Three researchers ran a database query in PubMed, Web of Science and EMBASE. The total number of patients considered was 488. The most often used parameters of response to therapy were the reductions in the maximum standardized uptake value (SUVmax) or the peak standardized uptake lean mass (SULpeak). Patients whose SUVs were higher at the baseline (before CRT) were associated with a better response to therapy and a better overall survival. SUVs remaining high after neoadjuvant therapy correlated with a poor prognosis. Available data indicate that FDG PET/CT or PET/MRI can be useful for predicting and assessing response to CRT in patients with resectable or borderline PDAC.
    Keywords:  FDG; Neoadjuvant therapy; PET/CT; PET/MRI; Pancreatic cancer
    DOI:  https://doi.org/10.1007/s12149-021-01629-0
  31. STAR Protoc. 2021 Jun 18. 2(2): 100535
    Using redox-sensitive fluorescent probes to record real-time reactive oxygen species production in cells from mouse carotid body slices.
    Lin Gao, Ignacio Arias-Mayenco, Patricia Ortega-Sáenz, José López-Barneo.
      Reactive oxygen species (ROS) are important signaling molecules for physiologic processes such as acute response to hypoxia. However, reliable real-time ROS measurement in cells has been a long-standing methodological challenge. Here, we present a protocol to record acute changes in ROS production in sensory cells from mouse carotid body (CB) slices using redox-sensitive green fluorescent protein probes and microfluorimetry. This protocol provides sensitive and reproducible quantification of ROS during acute hypoxia in different subcellular compartments of CB glomus cells. For complete details on the use and execution of this protocol, please refer to Fernández-Agüera et al. (2015) and Arias-Mayenco et al. (2018).
    Keywords:  Cell Biology; Metabolism; Microscopy; Molecular/Chemical Probes
    DOI:  https://doi.org/10.1016/j.xpro.2021.100535
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