bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022–06–05
eightteen papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Complementary omics strategies to dissect p53 signaling networks under nutrient stress.
  2. A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression.
  3. The fate of autophagosomal membrane components.
  4. Glycogen-autophagy: Molecular machinery and cellular mechanisms of glycophagy.
  5. Metabolic Reprogramming in Adipose Tissue During Cancer Cachexia.
  6. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability.
  7. Spatiotemporal multiplexed immunofluorescence imaging of living cells and tissues with bioorthogonal cycling of fluorescent probes.
  8. A Phase I/II Study of Ivaltinostat Combined with Gemcitabine and Erlotinib in Patients with Untreated Locally Advanced or Metastatic Pancreatic Adenocarcinoma.
  9. Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer.
  10. Circulating tumor and invasive cell expression profiling predicts effective therapy in pancreatic cancer.
  11. Stromal changes in the aged lung induce an emergence from melanoma dormancy.
  12. SRC plays a specific role in the cross-talk between apoptosis and autophagy via phosphorylation of a novel regulatory site on AMPK.
  13. Hypoxia-inducible factors: cancer progression and clinical translation.
  14. Branching Off: New Insight Into Lysosomes as Tubular Organelles.
  15. Non-canonical mTORC1 signaling at the lysosome.
  16. Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights.
  17. Denervation-induced muscle atrophy - saved by the lysosomes.
  18. Dusquetide modulates innate immune response through binding to p62.
  1. Cell Mol Life Sci. 2022 May 30. 79(6): 326
    Complementary omics strategies to dissect p53 signaling networks under nutrient stress.
    Markus Galhuber, Helene Michenthaler, Christoph Heininger, Isabel Reinisch, Christoph Nössing, Jelena Krstic, Nadja Kupper, Elisabeth Moyschewitz, Martina Auer, Ellen Heitzer, Peter Ulz, Ruth Birner-Gruenberger, Laura Liesinger, Georgia Ngawai Lenihan-Geels, Moritz Oster, Emil Spreitzer, Riccardo Zenezini Chiozzi, Tim J Schulz, Michael Schupp, Tobias Madl, Albert J R Heck, Andreas Prokesch.
      Signaling trough p53is a major cellular stress response mechanism and increases upon nutrient stresses such as starvation. Here, we show in a human hepatoma cell line that starvation leads to robust nuclear p53 stabilization. Using BioID, we determine the cytoplasmic p53 interaction network within the immediate-early starvation response and show that p53 is dissociated from several metabolic enzymes and the kinase PAK2 for which direct binding with the p53 DNA-binding domain was confirmed with NMR studies. Furthermore, proteomics after p53 immunoprecipitation (RIME) uncovered the nuclear interactome under prolonged starvation, where we confirmed the novel p53 interactors SORBS1 (insulin receptor signaling) and UGP2 (glycogen synthesis). Finally, transcriptomics after p53 re-expression revealed a distinct starvation-specific transcriptome response and suggested previously unknown nutrient-dependent p53 target genes. Together, our complementary approaches delineate several nodes of the p53 signaling cascade upon starvation, shedding new light on the mechanisms of p53 as nutrient stress sensor. Given the central role of p53 in cancer biology and the beneficial effects of fasting in cancer treatment, the identified interaction partners and networks could pinpoint novel pharmacologic targets to fine-tune p53 activity.
    Keywords:  Interactome; Nutrient stress; Starvation; p53 signaling; p53 targets
    DOI:  https://doi.org/10.1007/s00018-022-04345-8
  2. Nat Cell Biol. 2022 Jun 02.
    A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression.
    Ioannis I Verginadis, Harris Avgousti, James Monslow, Giorgos Skoufos, Frank Chinga, Kyle Kim, Nektaria Maria Leli, Ilias V Karagounis, Brett I Bell, Anastasia Velalopoulou, Carlo Salas Salinas, Victoria S Wu, Yang Li, Jiangbin Ye, David A Scott, Andrei L Osterman, Arjun Sengupta, Aalim Weljie, Menggui Huang, Duo Zhang, Yi Fan, Enrico Radaelli, John W Tobias, Florian Rambow, Panagiotis Karras, Jean-Christophe Marine, Xiaowei Xu, Artemis G Hatzigeorgiou, Sandra Ryeom, J Alan Diehl, Serge Y Fuchs, Ellen Puré, Constantinos Koumenis.
      Bidirectional signalling between the tumour and stroma shapes tumour aggressiveness and metastasis. ATF4 is a major effector of the Integrated Stress Response, a homeostatic mechanism that couples cell growth and survival to bioenergetic demands. Using conditional knockout ATF4 mice, we show that global, or fibroblast-specific loss of host ATF4, results in deficient vascularization and a pronounced growth delay of syngeneic melanoma and pancreatic tumours. Single-cell transcriptomics of tumours grown in Atf4Δ/Δ mice uncovered a reduction in activation markers in perivascular cancer-associated fibroblasts (CAFs). Atf4Δ/Δ fibroblasts displayed significant defects in collagen biosynthesis and deposition and a reduced ability to support angiogenesis. Mechanistically, ATF4 regulates the expression of the Col1a1 gene and levels of glycine and proline, the major amino acids of collagen. Analyses of human melanoma and pancreatic tumours revealed a strong correlation between ATF4 and collagen levels. Our findings establish stromal ATF4 as a key driver of CAF functionality, malignant progression and metastasis.
    DOI:  https://doi.org/10.1038/s41556-022-00918-8
  3. Autophagy. 2022 Jun 02. 1-2
    The fate of autophagosomal membrane components.
    Zhe Wu, Chuchu Zhou, Huilin Que, Yufen Wang, Yueguang Rong.
      During macroautophagy/autophagy, autophagosomes fuse with lysosomes to form autolysosomes. After fusion, the autophagosome inner membrane and enclosed substrates are degraded and transported out of lysosomes for recycling. The lysosomal membrane components are recycled by autophagic lysosome reformation (ALR) to generate new lysosomes. However, the fate of autophagosome outer membrane components on autolysosomes remains unknown. Our recent work discovered that autophagosome outer membrane components are not degraded but are recycled through an unidentified process which we named autophagosomal components recycling (ACR). Further investigation revealed the recycler complex (SNX4-SNX5-SNX17) responsible for ACR. The discovery of ACR not only fills a missing part in autophagy, but also reveals a new recycling pathway on autolysosomes.
    Keywords:  ATG9A; STX17; autophagosomal components recycling; autophagy; lysosome
    DOI:  https://doi.org/10.1080/15548627.2022.2083807
  4. J Biol Chem. 2022 May 30. pii: S0021-9258(22)00534-8. [Epub ahead of print] 102093
    Glycogen-autophagy: Molecular machinery and cellular mechanisms of glycophagy.
    Parisa Koutsifeli, Upasna Varma, Lorna J Daniels, Marco Annandale, Xun Li, Joshua P H Neale, Sarah Hayes, Kate L Weeks, Samuel James, Lea M D Delbridge, Kimberley M Mellor.
      Autophagy is an essential cellular process involving degradation of superfluous or defective macromolecules and organelles as a form of homeostatic recycling. Initially proposed to be a 'bulk' degradation pathway, a more nuanced appreciation of selective autophagy pathways has developed in the literature in recent years. As a glycogen-selective autophagy process, 'glycophagy' is emerging as a key metabolic route of transport and delivery of glycolytic fuel substrate. Study of glycophagy is at an early stage. Enhanced understanding of this major non-canonical pathway of glycogen flux will provide important opportunities for new insights into cellular energy metabolism. In addition, glycogen metabolic mishandling is centrally involved in the pathophysiology of several metabolic diseases in a wide range of tissues, including liver, skeletal muscle, cardiac muscle, and brain. Thus, advances in this exciting new field are of broad multi-disciplinary interest relevant to many cell types and metabolic states. Here, we review the current evidence of glycophagy involvement in homeostatic cellular metabolic processes and of molecular mediators participating in glycophagy flux, We integrate information from a variety of settings including cell lines, primary cell culture systems, ex vivo tissue preparations, genetic disease models and clinical glycogen disease states.
    Keywords:  Atg8; Gabarapl1; Stbd1; autophagy; glycogen; glycophagy; lysosome
    DOI:  https://doi.org/10.1016/j.jbc.2022.102093
  5. Front Oncol. 2022 ;12 848394
    Metabolic Reprogramming in Adipose Tissue During Cancer Cachexia.
    Bahar Zehra Camurdanoglu Weber, Dilsad H Arabaci, Serkan Kir.
      Cancer cachexia is a disorder of energy balance characterized by the wasting of adipose tissue and skeletal muscle resulting in severe weight loss with profound influence on morbidity and mortality. Treatment options for cancer cachexia are still limited. This multifactorial syndrome is associated with changes in several metabolic pathways in adipose tissue which is affected early in the course of cachexia. Adipose depots are involved in energy storage and consumption as well as endocrine functions. In this mini review, we discuss the metabolic reprogramming in all three types of adipose tissues - white, brown, and beige - under the influence of the tumor macro-environment. Alterations in adipose tissue lipolysis, lipogenesis, inflammation and adaptive thermogenesis of beige/brown adipocytes are highlighted. Energy-wasting circuits in adipose tissue impacts whole-body metabolism and particularly skeletal muscle. Targeting of key molecular players involved in the metabolic reprogramming may aid in the development of new treatment strategies for cancer cachexia.
    Keywords:  adipokines; adipose tissue; adipose tissue browning; cancer cachexia; inflammation; lipogenesis; lipolysis; non-shivering thermogenesis
    DOI:  https://doi.org/10.3389/fonc.2022.848394
  6. Nat Chem Biol. 2022 May 30.
    Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability.
    Zhipeng Li, Lucas Ferguson, Kirandeep K Deol, Melissa A Roberts, Leslie Magtanong, Joseph M Hendricks, Gergey Alzaem Mousa, Seda Kilinc, Kaitlin Schaefer, James A Wells, Michael C Bassik, Andrei Goga, Scott J Dixon, Nicholas T Ingolia, James A Olzmann.
      The selenoprotein glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid peroxides into nontoxic lipid alcohols. GPX4 has emerged as a promising therapeutic target for cancer treatment, but some cancer cells are resistant to ferroptosis triggered by GPX4 inhibition. Using a chemical-genetic screen, we identify LRP8 (also known as ApoER2) as a ferroptosis resistance factor that is upregulated in cancer. Loss of LRP8 decreases cellular selenium levels and the expression of a subset of selenoproteins. Counter to the canonical hierarchical selenoprotein regulatory program, GPX4 levels are strongly reduced due to impaired translation. Mechanistically, low selenium levels result in ribosome stalling at the inefficiently decoded GPX4 selenocysteine UGA codon, leading to ribosome collisions, early translation termination and proteasomal clearance of the N-terminal GPX4 fragment. These findings reveal rewiring of the selenoprotein hierarchy in cancer cells and identify ribosome stalling and collisions during GPX4 translation as ferroptosis vulnerabilities in cancer.
    DOI:  https://doi.org/10.1038/s41589-022-01033-3
  7. Nat Biotechnol. 2022 Jun 02.
    Spatiotemporal multiplexed immunofluorescence imaging of living cells and tissues with bioorthogonal cycling of fluorescent probes.
    Jina Ko, Martin Wilkovitsch, Juhyun Oh, Rainer H Kohler, Evangelia Bolli, Mikael J Pittet, Claudio Vinegoni, David B Sykes, Hannes Mikula, Ralph Weissleder, Jonathan C T Carlson.
      Cells in complex organisms undergo frequent functional changes, but few methods allow comprehensive longitudinal profiling of living cells. Here we introduce scission-accelerated fluorophore exchange (SAFE), a method for multiplexed temporospatial imaging of living cells with immunofluorescence. SAFE uses a rapid bioorthogonal click chemistry to remove immunofluorescent signals from the surface of labeled cells, cycling the nanomolar-concentration reagents in seconds and enabling multiple rounds of staining of the same samples. It is non-toxic and functional in both dispersed cells and intact living tissues. We demonstrate multiparameter (n ≥ 14), non-disruptive imaging of murine peripheral blood mononuclear and bone marrow cells to profile cellular differentiation. We also show longitudinal multiplexed imaging of bone marrow progenitor cells as they develop into neutrophils over 6 days and real-time multiplexed cycling of living mouse hepatic tissues. We anticipate that SAFE will find broad utility for investigating physiologic dynamics in living systems.
    DOI:  https://doi.org/10.1038/s41587-022-01339-6
  8. Int J Cancer. 2022 Jun 03.
    A Phase I/II Study of Ivaltinostat Combined with Gemcitabine and Erlotinib in Patients with Untreated Locally Advanced or Metastatic Pancreatic Adenocarcinoma.
    Jung Hyun Jo, Dawoon E Jung, Hee Seung Lee, Soo Been Park, Moon Jae Chung, Jeong Youp Park, Seungmin Bang, Seung Woo Park, Sangsook Cho, Si Young Song.
      This phase I/II study evaluated the safety and efficacy of a new histone deacetylase (HDAC) inhibitor, ivaltinostat, in combination with gemcitabine and erlotinib for advanced pancreatic ductal adenocarcinoma (PDAC). Patients diagnosed with unresectable, histologically confirmed PDAC who had not undergone previous therapy were eligible. Phase I had a 3+3 dose escalation design to determine the maximum tolerable dose (MTD) of ivaltinostat (intravenously on days 1, 8, and 15) with gemcitabine (1000 mg/m2 intravenously on days 1, 8, and 15) and erlotinib (100 mg/day, orally) for a 28-day cycle. In phase II, patients received a six-cycle treatment with the MTD of ivaltinostat determined in phase I. The primary endpoint was the objective response rate (ORR). Secondary endpoints included overall survival (OS), disease control rate (DCR), and progression-free survival (PFS). The MTD of ivaltinostat for the phase II trial was determined to be 250 mg/m2 . In phase II, 24 patients were enrolled. The median OS and PFS were 8.6 (95% confidence interval [CI]: 5.3-11.2) and 5.3 months (95% CI: 3.7-5.8). Of the 16 patients evaluated for response, ORR and DCR were 25.0% and 93.8% with a median OS/PFS of 10.8 (95% CI: 8.3-16.7)/5.8 (95% CI: 4.6-6.7) months. Correlative studies showed that mutation burden detected by cfDNA and specific blood markers such as TIMP1, pro-MMP10, PECAM1, proMMP-2, and IGFBP1 were associated with clinical outcomes. Although the result of a small study, a combination of ivaltinostat, gemcitabine, and erlotinib appeared to be a potential treatment option for advanced PDAC.
    Keywords:  chemotherapy; erlotinib; gemcitabine; ivaltinostat; pancreatic cancer
    DOI:  https://doi.org/10.1002/ijc.34144
  9. N Engl J Med. 2022 Jun 02. 386(22): 2112-2119
    Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer.
    Rom Leidner, Nelson Sanjuan Silva, Huayu Huang, David Sprott, Chunhong Zheng, Yi-Ping Shih, Amy Leung, Roxanne Payne, Kim Sutcliffe, Julie Cramer, Steven A Rosenberg, Bernard A Fox, Walter J Urba, Eric Tran.
      A patient with progressive metastatic pancreatic cancer was treated with a single infusion of 16.2×109 autologous T cells that had been genetically engineered to clonally express two allogeneic HLA-C*08:02-restricted T-cell receptors (TCRs) targeting mutant KRAS G12D expressed by the tumors. The patient had regression of visceral metastases (overall partial response of 72% according to the Response Evaluation Criteria in Solid Tumors, version 1.1); the response was ongoing at 6 months. The engineered T cells constituted more than 2% of all the circulating peripheral-blood T cells 6 months after the cell transfer. In this patient, TCR gene therapy targeting the KRAS G12D driver mutation mediated the objective regression of metastatic pancreatic cancer. (Funded by the Providence Portland Medical Foundation.).
    DOI:  https://doi.org/10.1056/NEJMoa2119662
  10. Cancer. 2022 Jun 01.
    Circulating tumor and invasive cell expression profiling predicts effective therapy in pancreatic cancer.
    Kenneth H Yu, Jennifer Park, Avni Mittal, Ghassan K Abou-Alfa, Imane El Dika, Andrew S Epstein, David H Ilson, David P Kelsen, Geoffrey Y Ku, Jia Li, Wungki Park, Anna M Varghese, Joanne F-L Chou, Marinela Capanu, Brandon Cooper, Andrew Bartlett, Devan McCarthy, Vineet Sangar, Brian McCarthy, Eileen M O'Reilly.
       BACKGROUND: Pancreatic adenocarcinoma (PDAC) remains a refractory disease; however, modern cytotoxic chemotherapeutics can induce tumor regression and extend life. A blood-based, pharmacogenomic, chemosensitivity assay using gene expression profiling of circulating tumor and invasive cells (CTICs) to predict treatment response was previously developed. The combination regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel (G/nab-P) are established frontline approaches for treating advanced PDAC; however, there are no validated biomarkers for treatment selection. A similar unmet need exists for choosing second-line therapy.
    METHODS: The chemosensitivity assay was evaluated in metastatic PDAC patients presenting for frontline treatment. A prospective study enrolled patients (n = 70) before receiving either FOLFIRINOX or G/nab-P at a 1:1 ratio. Six milliliters of peripheral blood was collected at baseline and at time of disease progression. CTICs were isolated, gene-expression profiling was performed, and the assay was used to predict effective and ineffective chemotherapeutic agents. Treating physicians were blinded to the assay prediction results.
    RESULTS: Patients receiving an effective regimen as predicted by the chemosensitivity assay experienced significantly longer median progression-free survival (mPFS; 7.8 months vs. 4.2 months; hazard ratio [HR], 0.35; p = .0002) and median overall survival (mOS; 21.0 months vs. 9.7 months; HR, 0.40; p = .005), compared with an ineffective regimen. Assay prediction for effective second-line therapy was explored. The entire study cohort experienced favorable outcomes compared with historical controls, 7.1-month mPFS and 12.3-month mOS.
    CONCLUSIONS: Chemosensitivity assay profiling is a promising tool for guiding therapy in advanced PDAC. Further prospective validation is under way (clinicaltrials.gov NCT03033927).
    Keywords:  chemotherapy; circulating tumor and invasive cells; gene expression modeling; pancreatic cancer; personalized medicine
    DOI:  https://doi.org/10.1002/cncr.34269
  11. Nature. 2022 Jun 01.
    Stromal changes in the aged lung induce an emergence from melanoma dormancy.
    Mitchell E Fane, Yash Chhabra, Gretchen M Alicea, Devon A Maranto, Stephen M Douglass, Marie R Webster, Vito W Rebecca, Gloria E Marino, Filipe Almeida, Brett L Ecker, Daniel J Zabransky, Laura Hüser, Thomas Beer, Hsin-Yao Tang, Andrew Kossenkov, Meenhard Herlyn, David W Speicher, Wei Xu, Xiaowei Xu, Elizabeth M Jaffee, Julio A Aguirre-Ghiso, Ashani T Weeraratna.
      Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells-in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1-3. It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing4-8. We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung.
    DOI:  https://doi.org/10.1038/s41586-022-04774-2
  12. Autophagy Rep. 2022 ;1(1): 38-41
    SRC plays a specific role in the cross-talk between apoptosis and autophagy via phosphorylation of a novel regulatory site on AMPK.
    Ming Zhao, Darren Finlay, Robert Liddington, Kristiina Vuori.
      Cell detachment from the extracellular matrix (ECM) typically promotes cell death via a form of apoptosis known as anoikis. However, in tumor cells, detachment can also induce cell survival, utilizing a process known as macroautophagy/autophagy, which involves degradation and removal of apoptotic proteins as well as rewiring of metabolic pathways so that cells can survive under stress. The crosstalk between the competing processes of anoikis and autophagy is only partially understood but may be critical for the design of multi-drug therapeutic strategies. Here, we summarize our recent studies, which reveal a direct regulatory link between a major mediator of cell survival in adherent cells, the ECM-integrin-activated dual tyrosine kinase complex of SRC and PTK2/FAK, and a major regulator of cell metabolism and autophagy, AMP-activated protein kinase (AMPK). We identify a novel SRC phosphorylation site on AMPK and demonstrate that this phosphorylation event plays key roles in AMPK regulation, autophagy induction, and cell survival.
    Keywords:  AMPK; PTK2/FAK; SRC; apoptosis; autophagy; cell attachment; cell detachment; phosphorylation
    DOI:  https://doi.org/10.1080/27694127.2022.2047266
  13. J Clin Invest. 2022 Jun 01. pii: e159839. [Epub ahead of print]132(11):
    Hypoxia-inducible factors: cancer progression and clinical translation.
    Elizabeth E Wicks, Gregg L Semenza.
      Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.
    DOI:  https://doi.org/10.1172/JCI159839
  14. Front Cell Dev Biol. 2022 ;10 863922
    Branching Off: New Insight Into Lysosomes as Tubular Organelles.
    K Adam Bohnert, Alyssa E Johnson.
      Lysosomes are acidic, membrane-bound organelles that play essential roles in cellular quality control, metabolism, and signaling. The lysosomes of a cell are commonly depicted as vesicular organelles. Yet, lysosomes in fact show a high degree of ultrastructural heterogeneity. In some biological contexts, lysosome membranes naturally transform into tubular, non-vesicular morphologies. Though the purpose and regulation of tubular lysosomes has been historically understudied, emerging evidence suggests that tubular lysosomes may carry out unique activities, both degradative and non-degradative, that are critical to cell behavior, function, and viability. Here, we discuss recent advances in understanding the biological significance of tubular lysosomes in cellular physiology, and we highlight a growing number of examples that indicate the centrality of this special class of lysosomes to health and disease.
    Keywords:  aging; autophagy; cell biology; lysosome morphology; organelles; tubular lysosomes
    DOI:  https://doi.org/10.3389/fcell.2022.863922
  15. Trends Cell Biol. 2022 May 30. pii: S0962-8924(22)00117-9. [Epub ahead of print]
    Non-canonical mTORC1 signaling at the lysosome.
    Gennaro Napolitano, Chiara Di Malta, Andrea Ballabio.
      The mechanistic target of rapamycin complex 1 (mTORC1) signaling hub integrates multiple environmental cues to modulate cell growth and metabolism. Over the past decade considerable knowledge has been gained on the mechanisms modulating mTORC1 lysosomal recruitment and activation. However, whether and how mTORC1 is able to elicit selective responses to diverse signals has remained elusive until recently. We discuss emerging evidence for a 'non-canonical' mTORC1 signaling pathway that controls the function of microphthalmia/transcription factor E (MiT-TFE) transcription factors, key regulators of cell metabolism. This signaling pathway is mediated by a specific mechanism of substrate recruitment, and responds to stimuli that appear to converge on the lysosomal surface. We discuss the relevance of this pathway in physiological and disease conditions.
    Keywords:  FLCN; Rag GTPases; TFEB; lysosome; mTORC1
    DOI:  https://doi.org/10.1016/j.tcb.2022.04.012
  16. Br J Cancer. 2022 Jun 01.
    Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights.
    Emily Latacz, Diederik Höppener, Ali Bohlok, Sophia Leduc, Sébastien Tabariès, Carlos Fernández Moro, Claire Lugassy, Hanna Nyström, Béla Bozóky, Giuseppe Floris, Natalie Geyer, Pnina Brodt, Laura Llado, Laura Van Mileghem, Maxim De Schepper, Ali W Majeed, Anthoula Lazaris, Piet Dirix, Qianni Zhang, Stéphanie K Petrillo, Sophie Vankerckhove, Ines Joye, Yannick Meyer, Alexander Gregorieff, Nuria Ruiz Roig, Fernando Vidal-Vanaclocha, Larsimont Denis, Rui Caetano Oliveira, Peter Metrakos, Dirk J Grünhagen, Iris D Nagtegaal, David G Mollevi, William R Jarnagin, Michael I D'Angelica, Andrew R Reynolds, Michail Doukas, Christine Desmedt, Luc Dirix, Vincent Donckier, Peter M Siegel, Raymond Barnhill, Marco Gerling, Cornelis Verhoef, Peter B Vermeulen.
      The first consensus guidelines for scoring the histopathological growth patterns (HGPs) of liver metastases were established in 2017. Since then, numerous studies have applied these guidelines, have further substantiated the potential clinical value of the HGPs in patients with liver metastases from various tumour types and are starting to shed light on the biology of the distinct HGPs. In the present guidelines, we give an overview of these studies, discuss novel strategies for predicting the HGPs of liver metastases, such as deep-learning algorithms for whole-slide histopathology images and medical imaging, and highlight liver metastasis animal models that exhibit features of the different HGPs. Based on a pooled analysis of large cohorts of patients with liver-metastatic colorectal cancer, we propose a new cut-off to categorise patients according to the HGPs. An up-to-date standard method for HGP assessment within liver metastases is also presented with the aim of incorporating HGPs into the decision-making processes surrounding the treatment of patients with liver-metastatic cancer. Finally, we propose hypotheses on the cellular and molecular mechanisms that drive the biology of the different HGPs, opening some exciting preclinical and clinical research perspectives.
    DOI:  https://doi.org/10.1038/s41416-022-01859-7
  17. J Physiol. 2022 Jun 02.
    Denervation-induced muscle atrophy - saved by the lysosomes.
    Emma Frank.
      
    Keywords:  denervation; lysosomes; mitochondria; mitophagy; muscle atrophy
    DOI:  https://doi.org/10.1113/JP283207
  18. Structure. 2022 May 19. pii: S0969-2126(22)00177-0. [Epub ahead of print]
    Dusquetide modulates innate immune response through binding to p62.
    Yi Zhang, Christina G Towers, Upendra K Singh, Jiuyang Liu, Maria Håkansson, Derek T Logan, Oreola Donini, Tatiana G Kutateladze.
      SQSTM1/p62 is an autophagic receptor that plays a major role in mediating stress and innate immune responses. Preclinical studies identified p62 as a target of the prototype innate defense regulator (IDR); however, the molecular mechanism of this process remains unclear. Here, we describe the structural basis and biological consequences of the interaction of p62 with the next generation of IDRs, dusquetide. Both electrostatic and hydrophobic contacts drive the formation of the complex between dusquetide and the ZZ domain of p62. We show that dusquetide penetrates the cell membrane and associates with p62 in vivo. Dusquetide binding modulates the p62-RIP1 complex, increases p38 phosphorylation, and enhances CEBP/B expression without activating autophagy. Our findings provide molecular details underlying the IDR action that may help in the development of new strategies to pharmacologically target p62.
    Keywords:  IDR; ZZ domain; dusquetide; innate immune response; p62
    DOI:  https://doi.org/10.1016/j.str.2022.05.003
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