bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2021‒12‒26
thirty-five papers selected by
Kıvanç Görgülü
Technical University of Munich

  1. Elife. 2021 Dec 24. pii: e62645. [Epub ahead of print]10
      Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in human PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not preclude the growth of human tumor xenografts in mice, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. We found that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.
    Keywords:  cancer biology; human; mouse
  2. Mol Oncol. 2021 Dec 23.
      For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRASG12C inhibitors represents a landmark after 40 years of intense research efforts since the identification of KRAS as a human oncogene. Here, we discuss the mechanisms responsible for the rapid development of resistance to these inhibitors, as well as potential strategies to overcome this limitation. Other therapeutic strategies aimed at inhibiting KRAS oncogenic signaling by targeting either upstream activators or downstream effectors are also reviewed. Finally, we discuss the effect of targeting the MAPK pathway, both based on the failure of MEK and ERK inhibitors in clinical trials, as well as on the recent identification of RAF1 as a potential target due to its MAPK-independent activity. These new developments, taken together, are likely to open new avenues to effectively treat KRAS mutant LUAD.
    Keywords:  KRASG12C inhibitors; Lung adenocarcinoma; RAF1; RAS signaling; genetically engineered mouse tumor models; tumor resistance
  3. Gastroenterology. 2021 Dec 16. pii: S0016-5085(21)04077-4. [Epub ahead of print]
      BACKGROUND AND AIMS: Acinar to Ductal Metaplasia (ADM) is the prerequisite for the initiation of Kras-driven pancreatic adenocarcinoma (PDAC) and candidate genes regulating this process are emerging from GWAS studies. The adaptor protein p130Cas emerged as a potential PDAC susceptibility gene and a Kras-synthetic lethal interactor in pancreatic cell lines, however its role in PDAC development has remained largely unknown.METHODS: Human PDAC samples and murine KrasG12D-dependent pancreatic cancer models of increasing aggressiveness were used. p130Cas was conditionally ablated in pancreatic cancer models to investigate its role during Kras-induced tumorigenesis RESULTS: Here, we show that high expression of p130Cas is frequently detected in Pancreatic ductal adenocarcinoma (PDAC) and correlates with higher histologic grade and poor prognosis. In a model of Kras-driven PDAC, loss of p130Cas inhibits tumor development and potently extends median survival. Deletion of p130Cas suppresses acinar-derived tumorigenesis and progression by repressing PI3K-AKT signaling, even in the presence of a worsening condition like pancreatitis.
    CONCLUSIONS: Our observations finally demonstrated that p130Cas acts downstream of Kras to boost the PI3K activity required for ADM and subsequent tumor initiation. This demonstrates an unexpected driving role of p130Cas downstream of Kras through the PI3K/AKT, thus indicating a rational therapeutic strategy of targeting the PI3K pathway in tumors with high expression of p130Cas.
    Keywords:  ADM; Kras; PDAC; carcinogenesis; metaplasia
  4. Cancer Biol Med. 2021 Dec 22. pii: j.issn.2095-3941.2021.0461. [Epub ahead of print]
      Metabolic remodeling is a key feature of cancer development. Knowledge of cancer metabolism has greatly expanded since the first observation of abnormal metabolism in cancer cells, the so-called Warburg effect. Malignant cells tend to modify cellular metabolism to favor specialized fermentation over the aerobic respiration usually used by most normal cells. Thus, targeted cancer therapies based on reprogramming nutrient or metabolite metabolism have received substantial attention both conceptually and in clinical practice. In particular, the management of nutrient availability is becoming more attractive in cancer treatment. In this review, we discuss recent findings on tumor metabolism and potential dietary interventions based on the specific characteristics of tumor metabolism. First, we present a comprehensive overview of changes in macronutrient metabolism. Carbohydrates, amino acids, and lipids, are rewired in the cancer microenvironment individually or systematically. Second, we summarize recent progress in cancer interventions applying different types of diets and specific nutrient restrictions in pre-clinical research or clinical trials.
    Keywords:  Cancer metabolism; amino acid; carbohydrate; diet intervention; lipid
  5. Science. 2021 Dec 24. 374(6575): 1632-1640
    Christine N Spencer, Jennifer L McQuade, Vancheswaran Gopalakrishnan, John A McCulloch, Marie Vetizou, Alexandria P Cogdill, Md A Wadud Khan, Xiaotao Zhang, Michael G White, Christine B Peterson, Matthew C Wong, Golnaz Morad, Theresa Rodgers, Jonathan H Badger, Beth A Helmink, Miles C Andrews, Richard R Rodrigues, Andrey Morgun, Young S Kim, Jason Roszik, Kristi L Hoffman, Jiali Zheng, Yifan Zhou, Yusra B Medik, Laura M Kahn, Sarah Johnson, Courtney W Hudgens, Khalida Wani, Pierre-Olivier Gaudreau, Angela L Harris, Mohamed A Jamal, Erez N Baruch, Eva Perez-Guijarro, Chi-Ping Day, Glenn Merlino, Barbara Pazdrak, Brooke S Lochmann, Robert A Szczepaniak-Sloane, Reetakshi Arora, Jaime Anderson, Chrystia M Zobniw, Eliza Posada, Elizabeth Sirmans, Julie Simon, Lauren E Haydu, Elizabeth M Burton, Linghua Wang, Minghao Dang, Karen Clise-Dwyer, Sarah Schneider, Thomas Chapman, Nana-Ama A S Anang, Sheila Duncan, Joseph Toker, Jared C Malke, Isabella C Glitza, Rodabe N Amaria, Hussein A Tawbi, Adi Diab, Michael K Wong, Sapna P Patel, Scott E Woodman, Michael A Davies, Merrick I Ross, Jeffrey E Gershenwald, Jeffrey E Lee, Patrick Hwu, Vanessa Jensen, Yardena Samuels, Ravid Straussman, Nadim J Ajami, Kelly C Nelson, Luigi Nezi, Joseph F Petrosino, P Andrew Futreal, Alexander J Lazar, Jianhua Hu, Robert R Jenq, Michael T Tetzlaff, Yan Yan, Wendy S Garrett, Curtis Huttenhower, Padmanee Sharma, Stephanie S Watowich, James P Allison, Lorenzo Cohen, Giorgio Trinchieri, Carrie R Daniel, Jennifer A Wargo.
      [Figure: see text].
  6. Elife. 2021 Dec 23. pii: e72593. [Epub ahead of print]10
      The Tricarboxylic Acid Cycle (TCA) cycle is arguably the most critical metabolic cycle in physiology and exists as an essential interface coordinating cellular metabolism, bioenergetics, and redox homeostasis. Despite decades of research, a comprehensive investigation into the consequences of TCA cycle dysfunction remains elusive. Here, we targeted two TCA cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), and combined metabolomics, transcriptomics, and proteomics analyses to fully appraise the consequences of TCA cycle inhibition (TCAi) in murine kidney epithelial cells. Our comparative approach shows that TCAi elicits a convergent rewiring of redox and amino acid metabolism dependent on the activation of ATF4 and the integrated stress response (ISR). Furthermore, we also uncover a divergent metabolic response, whereby acute FHi, but not SDHi, can maintain asparagine levels via reductive carboxylation and maintenance of cytosolic aspartate synthesis. Our work highlights an important interplay between the TCA cycle, redox biology and amino acid homeostasis.
    Keywords:  biochemistry; cell biology; chemical biology; mouse
  7. Curr Opin Syst Biol. 2021 Dec;28 None
      Circadian rhythms are ∼24 h cycles of organismal and cellular activity ubiquitous to mammalian physiology. A prevailing paradigm suggests that timing information flows linearly from rhythmic transcription via protein abundance changes to drive circadian regulation of cellular function. Challenging this view, recent evidence indicates daily variation in many cellular functions arises through rhythmic post-translational regulation of protein activity. We suggest cellular circadian timing primarily functions to maintain proteome homeostasis rather than perturb it. Indeed, although relevant to timekeeping mechanism, daily rhythms of clock protein abundance may be the exception, not the rule. Informed by insights from yeast and mammalian models, we propose that optimal bioenergetic efficiency results from coupled rhythms in mammalian target of rapamycin complex activity, protein synthesis/turnover, ion transport and protein sequestration, which drive facilitatory rhythms in metabolic flux and substrate utilisation. Such daily consolidation of proteome renewal would account for many aspects of circadian cell biology whilst maintaining osmotic homeostasis.
    Keywords:  Biological clock; Cellular function; Circadian rhythm; Homeostasis; Ion transport; Macromolecular crowding; Metabolic cycle; Metabolism; Osmostasis; Protein synthesis; Protein turnover; Respiratory oscillation; TORC
  8. Autophagy. 2021 Dec 19. 1-3
      Mitophagy, a type of selective autophagy targeting damaged or superfluous mitochondria, is critical to maintain cell homeostasis. Besides the well-characterized PRKN-dependent mitophagy, PRKN-independent mitophagy also plays significant physiological roles. In a recent study, researchers from Anne Simonsen's lab discovered two lipid binding kinases, GAK and PRKCD, as positive regulators of PRKN-independent mitophagy. The researchers further investigated how these two proteins regulate mitophagy and demonstrated their roles in vivo. Focusing on the less known PRKN-independent mitophagy regulators, these findings shed light on understanding the mechanism of mitophagy and its relation to diseases.
    Keywords:  Autophagy; GAK; PRKCD; PRKN; lipid-binding kinases
  9. Cancer Metastasis Rev. 2021 Dec 21.
      It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.
    Keywords:  Cancer-associated cells; Citrate; OXPHOS; Redox; Senescence; Warburg effect
  10. J Exp Med. 2022 Feb 07. pii: e20201966. [Epub ahead of print]219(2):
      T cell receptor (TCR) signal strength is a key determinant of T cell responses. We developed a cancer mouse model in which tumor-specific CD8 T cells (TST cells) encounter tumor antigens with varying TCR signal strength. High-signal-strength interactions caused TST cells to up-regulate inhibitory receptors (IRs), lose effector function, and establish a dysfunction-associated molecular program. TST cells undergoing low-signal-strength interactions also up-regulated IRs, including PD1, but retained a cell-intrinsic functional state. Surprisingly, neither high- nor low-signal-strength interactions led to tumor control in vivo, revealing two distinct mechanisms by which PD1hi TST cells permit tumor escape; high signal strength drives dysfunction, while low signal strength results in functional inertness, where the signal strength is too low to mediate effective cancer cell killing by functional TST cells. CRISPR-Cas9-mediated fine-tuning of signal strength to an intermediate range improved anti-tumor activity in vivo. Our study defines the role of TCR signal strength in TST cell function, with important implications for T cell-based cancer immunotherapies.
  11. Cancers (Basel). 2021 Dec 08. pii: 6188. [Epub ahead of print]13(24):
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely composed of cancer-associated fibroblasts (CAFs), immunosuppressive immune cells, immunoregulatory soluble factors, neural network cells, and endothelial cells with complex interactions. PDAC develops from various precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL). In this review, we focus on the composition of the TME in PanINs to reveal detailed insights into the complex restructuring of the TME at early time points in PDAC progression and to explore ways of modifying the TME to slow or even halt tumor progression.
    Keywords:  PDAC; PanIN; pancreatic cancer; tumor microenvironment
  12. Nature. 2021 Dec 22.
      Although deregulation of transfer RNA (tRNA) biogenesis promotes the translation of pro-tumorigenic mRNAs in cancers1,2, the mechanisms and consequences of tRNA deregulation in tumorigenesis are poorly understood. Here we use a CRISPR-Cas9 screen to focus on genes that have been implicated in tRNA biogenesis, and identify a mechanism by which altered valine tRNA biogenesis enhances mitochondrial bioenergetics in T cell acute lymphoblastic leukaemia (T-ALL). Expression of valine aminoacyl tRNA synthetase is transcriptionally upregulated by NOTCH1, a key oncogene in T-ALL, underlining a role for oncogenic transcriptional programs in coordinating tRNA supply and demand. Limiting valine bioavailability through restriction of dietary valine intake disrupted this balance in mice, resulting in decreased leukaemic burden and increased survival in vivo. Mechanistically, valine restriction reduced translation rates of mRNAs that encode subunits of mitochondrial complex I, leading to defective assembly of complex I and impaired oxidative phosphorylation. Finally, a genome-wide CRISPR-Cas9 loss-of-function screen in differential valine conditions identified several genes, including SLC7A5 and BCL2, whose genetic ablation or pharmacological inhibition synergized with valine restriction to reduce T-ALL growth. Our findings identify tRNA deregulation as a critical adaptation in the pathogenesis of T-ALL and provide a molecular basis for the use of dietary approaches to target tRNA biogenesis in blood malignancies.
  13. Nat Chem Biol. 2021 Dec 23.
      Small-molecule kinase inhibitors represent a major group of cancer therapeutics, but tumor responses are often incomplete. To identify pathways that modulate kinase inhibitor response, we conducted a genome-wide knockout (KO) screen in glioblastoma cells treated with the pan-ErbB inhibitor neratinib. Loss of general control nonderepressible 2 (GCN2) kinase rendered cells resistant to neratinib, whereas depletion of the GADD34 phosphatase increased neratinib sensitivity. Loss of GCN2 conferred neratinib resistance by preventing binding and activation of GCN2 by neratinib. Several other Food and Drug Administration (FDA)-approved inhibitors, such erlotinib and sunitinib, also bound and activated GCN2. Our results highlight the utility of genome-wide functional screens to uncover novel mechanisms of drug action and document the role of the integrated stress response (ISR) in modulating the response to inhibitors of oncogenic kinases.
  14. J Appl Physiol (1985). 2021 Dec 23.
      Reductions in skeletal muscle mass and function are often reported in patients with cancer-associated weight loss and are associated with reduced quality of life, impaired treatment tolerance, and increased mortality. Although cellular changes, including altered mitochondrial function, have been reported in animals, such changes have been incompletely characterized in humans with cancer. Whole body and skeletal muscle physical function, skeletal muscle mitochondrial function and whole-body protein turnover were assessed in 8 patients with cancer-associated weight loss (10.1±4.2% body weight over 6-12 months) and 19 age-, sex-, and BMI-matched healthy controls to characterize skeletal muscle changes at the whole body, muscle, and cellular level. Potential pathways involved in cancer-induced alterations in metabolism and mitochondrial function were explored by interrogating skeletal muscle and plasma metabolomes. Despite similar lean mass compared to control participants, patients with cancer exhibited reduced habitual physical activity (57% fewer daily steps), cardiorespiratory fitness (22% lower VO2peak [mL/kg/min]) and leg strength (35% lower isokinetic knee extensor strength) and greater leg neuromuscular fatigue (36% greater decline in knee extensor torque). Concomitant with these functional declines, patients with cancer had lower mitochondrial oxidative capacity (25% lower State 3 O2 flux [pmol/s/mg tissue]) and ATP production (23% lower State 3 ATP production [pmol/s/mg tissue]) and alterations in phospholipid metabolite profiles indicative of mitochondrial abnormalities. Whole body protein turnover was unchanged. These findings demonstrate mitochondrial abnormalities concomitant with whole-body and skeletal muscle functional derangements associated with human cancer, supporting future work studying the role of mitochondria in the muscle deficits associated with cancer.
    Keywords:  cancer-associated weight loss; mitochondria; muscle strength; physical activity; skeletal muscle
  15. Proc Natl Acad Sci U S A. 2022 Jan 04. pii: e2111046118. [Epub ahead of print]119(1):
      Dormancy is an evolutionarily conserved protective mechanism widely observed in nature. A pathological example is found during cancer metastasis, where cancer cells disseminate from the primary tumor, home to secondary organs, and enter a growth-arrested state, which could last for decades. Recent studies have pointed toward the microenvironment being heavily involved in inducing, preserving, or ceasing this dormant state, with a strong focus on identifying specific molecular mechanisms and signaling pathways. Increasing evidence now suggests the existence of an interplay between intracellular as well as extracellular biochemical and mechanical cues in guiding such processes. Despite the inherent complexities associated with dormancy, proliferation, and growth of cancer cells and tumor tissues, viewing these phenomena from a physical perspective allows for a more global description, independent from many details of the systems. Building on the analogies between tissues and fluids and thermodynamic phase separation concepts, we classify a number of proposed mechanisms in terms of a thermodynamic metastability of the tumor with respect to growth. This can be governed by interaction with the microenvironment in the form of adherence (wetting) to a substrate or by mechanical confinement of the surrounding extracellular matrix. By drawing parallels with clinical and experimental data, we advance the notion that the local energy minima, or metastable states, emerging in the tissue droplet growth kinetics can be associated with a dormant state. Despite its simplicity, the provided framework captures several aspects associated with cancer dormancy and tumor growth.
    Keywords:  cancer dormancy; extracellular matrix; metastability; phase separation; tissue growth
  16. Int J Cancer. 2021 Dec 22.
    Dutch Pancreatic Cancer Group
      The added value of capecitabine to adjuvant gemcitabine monotherapy (GEM) in pancreatic ductal adenocarcinoma (PDAC) was shown by the ESPAC-4 trial. Real-world data on the effectiveness of gemcitabine plus capecitabine (GEMCAP), in patients inelegible for mFOLFIRINOX, are lacking. This study assessed whether adjuvant GEMCAP is superior to GEM in a nationwide cohort. Patients treated with adjuvant GEMCAP or GEM after resection of PDAC without preoperative treatment were identified from the Netherlands Cancer Registry (2015-2019). The primary outcome was overall survival (OS), measured from start of chemotherapy. The treatment effect of GEMCAP vs. GEM was adjusted for sex, age, performance status, tumor size, lymph node involvement, resection margin, and tumor differentiation in a multivariable Cox regression analysis. Secondary outcome was the percentage of patients who completed the planned six adjuvant treatment cycles. Overall, 778 patients were included, of whom 21.1% received GEMCAP and 78.9% received GEM. The median OS was 31.4 months (95% CI 26.8-40.7) for GEMCAP and 22.1 months (95% CI 20.6-25.0) for GEM (HR 0.71, 95% CI 0.56-0.90; logrank p=0.004). After adjustment for prognostic factors, survival remained superior for patients treated with GEMCAP (HR:0.73, 95% CI 0.57-0.92, logrank p=0.009). Survival with GEMCAP was superior to GEM in most subgroups of prognostic factors. Adjuvant chemotherapy was completed in 69.5% of the patients treated with GEMCAP and 62.7% with GEM (p=0.11). In this nationwide cohort of patients with PDAC, adjuvant GEMCAP was associated with superior survival as compared to GEM monotherapy and number of cycles was similar.
    Keywords:  Pancreatic cancer; chemotherapy; survival
  17. Cell. 2021 Dec 22. pii: S0092-8674(21)01386-6. [Epub ahead of print]184(26): 6226-6228
      Altered metabolism of tumors offers an opportunity to use metabolic interventions as a therapeutic strategy. Lien et al. demonstrate that understanding how specific diets with different carbohydrate and fat composition affect tumor metabolism is essential in order to use this opportunity efficiently.
  18. Front Cell Dev Biol. 2021 ;9 784424
      Unintentional weight loss, a first clinical sign of muscle wasting, is a major threat to cancer survival without a defined etiology. We previously identified in mice that p38β MAPK mediates cancer-induced muscle wasting by stimulating protein catabolism. However, whether this mechanism is relevant to humans is unknown. In this study, we recruited men with cancer and weight loss (CWL) or weight stable (CWS), and non-cancer controls (NCC), who were consented to rectus abdominis (RA) biopsy and blood sampling (n = 20/group). In the RA of both CWS and CWL, levels of activated p38β MAPK and its effectors in the catabolic pathways were higher than in NCC, with progressively higher active p38β MAPK detected in CWL. Remarkably, levels of active p38β MAPK correlated with weight loss. Plasma analysis for factors that activate p38β MAPK revealed higher levels in some cytokines as well as Hsp70 and Hsp90 in CWS and/or CWL. Thus, p38β MAPK appears a biomarker of weight loss in cancer patients.
    Keywords:  C/EBPbeta; Hsp70; Hsp90; P300; UBR2; ULK1
  19. Nat Cancer. 2021 Jul;2(7): 758-772
      Lineage-tracing methods have enabled characterization of clonal dynamics in complex populations, but generally lack the ability to integrate genomic, epigenomic and transcriptomic measurements with live-cell manipulation of specific clones of interest. We developed a functionalized lineage-tracing system, ClonMapper, which integrates DNA barcoding with single-cell RNA sequencing and clonal isolation to comprehensively characterize thousands of clones within heterogeneous populations. Using ClonMapper, we identified subpopulations of a chronic lymphocytic leukemia cell line with distinct clonal compositions, transcriptional signatures and chemotherapy survivorship trajectories; patterns that were also observed in primary human chronic lymphocytic leukemia. The ability to retrieve specific clones before, during and after treatment enabled direct measurements of clonal diversification and durable subpopulation transcriptional signatures. ClonMapper is a powerful multifunctional approach to dissect the complex clonal dynamics of tumor progression and therapeutic response.
  20. Molecules. 2021 Dec 14. pii: 7561. [Epub ahead of print]26(24):
      Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered on the exploration of inhibitors for RAS downstream effector kinases. Two major RAS downstream signaling pathways, including the Raf/MEK/Erk cascade and the phosphatidylinositol-3-kinase (PI3K) pathway, have become compelling targets for RAS-driven cancer therapy. However, the main drawback in the blockade of a single RAS effector is the multiple levels of crosstalk and compensatory mechanisms between these two pathways that contribute to drug resistance against monotherapies. A growing body of evidence reveals that the sequential or synergistic inhibition of multiple RAS effectors is a more convenient route for the efficacy of cancer therapy. Herein, we revisit the recent developments and discuss the most promising modalities targeting canonical RAS downstream effectors for the treatment of RAS-driven cancers.
    Keywords:  PI3K-mTOR; RAS effectors; RAS-driven cancers; Raf/MEK/Erk
  21. Am J Physiol Gastrointest Liver Physiol. 2021 Dec 22.
      Growth differentiation factor 15 (GDF15), a TGFβ superfamily cytokine, acts through its receptor, GDNF-family receptor α-like (GFRAL), to suppress food intake and promote nausea. GDF15 is broadly expressed at low levels but increases in states of disease such as cancer, cachexia, and sepsis. Whether GDF15 is necessary for inducing sepsis associated anorexia and body weight loss is currently unclear. To test this we used a model of moderate systemic infection in GDF15KO and GFRALKO mice with lipopolysaccharide (LPS) treatment to define the role of GDF15 signaling in infection-mediated physiologic responses. Since physiologic responses to LPS depend on housing temperature, we tested the effects of subthermoneutral and thermoneutral conditions on eliciting anorexia and inducing GDF15. Our data demonstrate a conserved LPS-mediated increase in circulating GDF15 levels in mouse, rat and human. However, we did not detect differences in LPS induced anorexia between WT and GDF15KO or GFRALKO mice. Further, there were no differences in anorexia or circulating GDF15 levels at either thermoneutral or subthermoneutral housing conditions in LPS treated mice. These data demonstrate that GDF15 is not necessary to drive food intake suppression in response to moderate doses of LPS.
    Keywords:  GDF-15; GFRAL; LPS; anorexia; thermoneutrality
  22. J Cachexia Sarcopenia Muscle. 2021 Dec 22.
      BACKGROUND: During cancer cachexia, several alterations occur in peripheral tissues, and the adipose tissue may be involved during the catabolic state. We aimed at investigating histological rearrangement and infiltration of inflammatory cells in subcutaneous adipose tissue (SAT) of patients with cancer undergoing surgery, according to the presence/absence of cachexia.METHODS: We considered gastrointestinal cancer patients and controls with non-malignant diseases undergoing surgery. We collected SAT samples and performed histomorphological analyses [cross-sectional area (CSA) and per cent of fibrosis] and immunohistochemistry to characterize the inflammatory cells. By computed tomography (CT) scan, we calculated SAT and visceral adipose tissue (VAT).
    RESULTS: We enrolled 51 participants (31 gastrointestinal cancer patients and 20 controls). In cancer patients, cachexia was present in 13/31 (42%). The CSA (μm2 ) of the adipocytes from SAT was reduced in cancer patients vs. controls (3148, inter-quartile range 2574-3755 vs. 4474, inter-quartile range 3654-5183) (P < 0.001), in particular in cachectic patients vs. non-cachectic (median 2518 vs. median 3470) (P = 0.03) and in cachectic vs. controls (P < 0.001), as well as in non-cachectic vs. controls (P = 0.04). The median per cent of fibrosis was higher in cancer patients vs. controls (9 vs. 3) (P = 0.0001), in particular in cachectic vs. non-cachectic (13.35 vs. 7.13) (P = 0.03). We observed a higher number of macrophages (CD68) (P = 0.0001) and T lymphocytes (CD3) (P = 0.002) in SAT of cancer patients vs. controls, and the number of T lymphocytes was higher in cachectic vs. non-cachectic patients (P = 0.025). Anorexic cancer patients showed in SAT a higher number of macrophages and T lymphocytes with respect to controls (P < 0.0001), whereas no difference was present between anorexic and non-anorexic patients. At CT scan, cachectic patients showed lower VAT and SAT vs. non-cachectic (VAT: 97.64 ± 40.79 vs. 212.53 ± 79.24, P = 0.0002; SAT: 126.27 ± 87.92 vs. 206.27 ± 61.93, P = 0.01, respectively). Cancer patients with low CSA, high degree of fibrosis, and high number of T lymphocytes presented with lower body mass index and lower SAT and VAT at CT scan (P ≤ 0.01).
    CONCLUSIONS: We found histological alterations of SAT among gastrointestinal cancer patients and in particular significant changes in CSA, fibrosis, and inflammation when cachexia was present; the changes in histomorphological parameters of the adipocytes reflected alterations in adiposity at body composition analysis.
    Keywords:  Adipose tissue; Body composition; Cachexia; Cancer; Fibrosis; Inflammation
  23. Cell Prolif. 2021 Dec 22. e13167
      Lipid rafts are cholesterol- and sphingolipid-enriched specialized membrane domains within the plasma membrane. Lipid rafts regulate the density and activity of signal receptors by compartmentalizing them, promoting signalling cascades that play important roles in the survival, death and metastasis of cancer cells. In this review, we emphasize the current concept initially postulated by F. Mollinedo and C. Gajate on the importance of lipid rafts in cancer survival, death and metastasis by describing representative signalling pathways, including the IGF system and the PI3K/AKT, Fas/CD95, VEGF/VEGFR2 and CD44 signalling pathways, and we also discuss the concept of CASMER (cluster of apoptotic signalling molecule-enriched rafts), coined, originally introduced and further advanced by F. Mollinedo and C. Gajate in the period 2005-2010. Then, we summarize relevant research progress and suggest that lipid rafts play important roles in the survival, death and metastasis of cancer cells, making them promising targets for cancer therapy.
    Keywords:  CD44; Fas/CD95; IGF-I/PI3K/Akt signalling; VEGF/VEGFR2; lipid rafts
  24. STAR Protoc. 2021 Dec 17. 2(4): 100989
      Preparation of single-cell suspension from primary tumor tissue can provide a valuable resource for functional, genetic, proteomic, and tumor microenvironment studies. Here, we describe an effective protocol for mouse pancreatic tumor dissociation with further processing of tumor suspension for single-cell RNA sequencing analysis of cellular populations. We further provide an outline of the bioinformatics processing of the data and clustering of heterogeneous cellular populations comprising pancreatic tumors using Common Workflow Language (CWL) pipelines within user-friendly Scientific Data Analysis Platform ( For complete details on the use and execution of this protocol, please refer to Gabitova-Cornell et al. (2020).
    Keywords:  Bioinformatics; Cancer; Cell Biology; Cell isolation; Molecular Biology; RNAseq; Sequence analysis; Single Cell
  25. Cell. 2021 Dec 22. pii: S0092-8674(21)01373-8. [Epub ahead of print]184(26): 6313-6325.e18
      How tissues acquire complex shapes is a fundamental question in biology and regenerative medicine. Zebrafish semicircular canals form from invaginations in the otic epithelium (buds) that extend and fuse to form the hubs of each canal. We find that conventional actomyosin-driven behaviors are not required. Instead, local secretion of hyaluronan, made by the enzymes uridine 5'-diphosphate dehydrogenase (ugdh) and hyaluronan synthase 3 (has3), drives canal morphogenesis. Charged hyaluronate polymers osmotically swell with water and generate isotropic extracellular pressure to deform the overlying epithelium into buds. The mechanical anisotropy needed to shape buds into tubes is conferred by a polarized distribution of actomyosin and E-cadherin-rich membrane tethers, which we term cytocinches. Most work on tissue morphogenesis ascribes actomyosin contractility as the driving force, while the extracellular matrix shapes tissues through differential stiffness. Our work inverts this expectation. Hyaluronate pressure shaped by anisotropic tissue stiffness may be a widespread mechanism for powering morphological change in organogenesis and tissue engineering.
    Keywords:  ECM; actomyosin; cadherin; hyaluronan; hyaluronic acid; hydraulics; inner ear; semicircular canals; tissue morphogenesis; zebrafish
  26. JCI Insight. 2021 Dec 22. pii: e154089. [Epub ahead of print]6(24):
      Ammonia is a cytotoxic metabolite with pleiotropic molecular and metabolic effects, including senescence induction. During dysregulated ammonia metabolism, which occurs in chronic diseases, skeletal muscle becomes a major organ for nonhepatocyte ammonia uptake. Muscle ammonia disposal occurs in mitochondria via cataplerosis of critical intermediary metabolite α-ketoglutarate, a senescence-ameliorating molecule. Untargeted and mitochondrially targeted data were analyzed by multiomics approaches. These analyses were validated experimentally to dissect the specific mitochondrial oxidative defects and functional consequences, including senescence. Responses to ammonia lowering in myotubes and in hyperammonemic portacaval anastomosis rat muscle were studied. Whole-cell transcriptomics integrated with whole-cell, mitochondrial, and tissue proteomics showed distinct temporal clusters of responses with enrichment of oxidative dysfunction and senescence-related pathways/proteins during hyperammonemia and after ammonia withdrawal. Functional and metabolic studies showed defects in electron transport chain complexes I, III, and IV; loss of supercomplex assembly; decreased ATP synthesis; increased free radical generation with oxidative modification of proteins/lipids; and senescence-associated molecular phenotype-increased β-galactosidase activity and expression of p16INK, p21, and p53. These perturbations were partially reversed by ammonia lowering. Dysregulated ammonia metabolism caused reversible mitochondrial dysfunction by transcriptional and translational perturbations in multiple pathways with a distinct skeletal muscle senescence-associated molecular phenotype.
    Keywords:  Cell Biology; Cellular senescence; Hepatology; Mitochondria; Skeletal muscle
  27. J Clin Med. 2021 Dec 10. pii: 5779. [Epub ahead of print]10(24):
      Exocrine pancreatic insufficiency (EPI), an important cause of maldigestion and malnutrition, results from primary pancreatic disease or is secondary to impaired exocrine pancreatic function. Although chronic pancreatitis is the most common cause of EPI, several additional causes exist. These include pancreatic tumors, pancreatic resection procedures, and cystic fibrosis. Other diseases and conditions, such as diabetes mellitus, celiac disease, inflammatory bowel disease, and advanced patient age, have also been shown to be associated with EPI, but the exact etiology of EPI has not been clearly elucidated in these cases. The causes of EPI can be divided into loss of pancreatic parenchyma, inhibition or inactivation of pancreatic secretion, and postcibal pancreatic asynchrony. Pancreatic enzyme replacement therapy (PERT) is indicated for the conditions described above presenting with clinically clear steatorrhea, weight loss, or symptoms related to maldigestion and malabsorption. This review summarizes the current literature concerning those etiologies of EPI less common than chronic pancreatitis, the pathophysiology of the mechanisms of EPI associated with each diagnosis, and treatment recommendations.
    Keywords:  celiac disease; cystic fibrosis; diabetes; exocrine pancreatic insufficiency; inflammatory bowel disease; microbiome; pancreatic cancer; pancreatic enzyme replacement therapy; pancreatic resection; surgery
  28. Front Oncol. 2021 ;11 771312
      Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10-5) compared with the additive effects (p>10-3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10-8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.
    Keywords:  genetic polymorphisms; genome-wide association study; pancreatic cancer; recessive model; susceptibility
  29. Cells. 2021 Dec 08. pii: 3449. [Epub ahead of print]10(12):
      Organ-specific proteins (OSPs) possess great medical potential both in clinics and in biomedical research. Applications of them-such as alanine transaminase, aspartate transaminase, and troponins-in clinics have raised certain concerns of their organ specificity. The dynamics and diversity of protein expression in heterogeneous human populations are well known, yet their effects on OSPs are less addressed. Here, we used mice as a model and implemented a breadth study to examine the panorgan proteome for potential variations in organ specificity in different genetic backgrounds. Using reasonable resources, we generated panorgan proteomes of four in-bred mouse strains. The results revealed a large diversity that was more profound among OSPs than among proteomes overall. We defined a robustness score to quantify such variation and derived three sets of OSPs with different stringencies. In the meantime, we found that the enriched biological functions of OSPs are also organ-specific and are sensitive and useful to assess the quality of OSPs. We hope our breadth study can open doors to explore the molecular diversity and dynamics of organ specificity at the protein level.
    Keywords:  biomarkers; bone proteome; brain proteome; eye proteome; fat proteome; heart proteome; intestine proteome; kidney proteome; liver proteome; lung proteome; mouse proteome; organ proteome; organ-specific proteins; pancreas proteome; proteome diversity; proteome dynamics; skeletal muscle proteome; spleen proteome; testis proteome
  30. Biophys J. 2021 Dec 21. pii: S0006-3495(21)03946-1. [Epub ahead of print]
      Metabolism is precisely coordinated, with the goal of balancing fluxes to maintain robust growth. However, coordinating fluxes requires information about rates, which can only be inferred through concentrations. While flux sensitive metabolites have been reported, the design principles underlying such sensing have not been clearly elucidated. Here we use kinetic modelling to show that substrate concentrations of thermodynamically constrained reactions reflect upstream flux and therefore carry information about rates. Then we use untargeted multi-omic data from E. coli and S. cerevisiae to show that the concentrations of some metabolites in central carbon metabolism reflect fluxes as a result of thermodynamic constraints. We then establish, using 37 real concentration-flux relationships across both organisms, that in vivo ΔG∘≥-4 kJ/mol is the threshold above which substrates are likely to be sensitive to upstream flux(es).
    Keywords:  design principles; metabolic regulation; metabolism; multi-omics; thermodynamics
  31. Front Cell Dev Biol. 2021 ;9 799123
      Focal adhesions (FAs) are adhesive organelles that attach cells to the extracellular matrix and can mediate various biological functions in response to different environmental cues. Reduced FAs are often associated with enhanced cell migration and cancer metastasis. In addition, because FAs are essential for preserving vascular integrity, the loss of FAs leads to hemorrhages and is frequently observed in many vascular diseases such as intracranial aneurysms. For these reasons, FAs are an attractive therapeutic target for treating cancer or vascular diseases, two leading causes of death world-wide. FAs are controlled by both their formation and turnover. In comparison to the large body of literature detailing FA formation, the mechanisms of FA turnover are poorly understood. Recently, autophagy has emerged as a major mechanism to degrade FAs and stabilizing FAs by inhibiting autophagy has a beneficial effect on breast cancer metastasis, suggesting autophagy-mediated FA turnover is a promising drug target. Intriguingly, autophagy-mediated FA turnover is a selective process and the cargo receptors for recognizing FAs in this process are context-dependent, which ensures the degradation of specific cargo. This paper mainly reviews the cargo recognition mechanisms of FA-phagy (selective autophagy-mediated FA turnover) and its disease relevance. We seek to outline some new points of understanding that will facilitate further study of FA-phagy and precise therapeutic strategies for related diseases associated with aberrant FA functions.
    Keywords:  autophagy; cancer; cargo receptor; focal adhesion; intracranial aneurysm; organellophagy; vascular integrity
  32. Cancer Discov. 2021 Dec 23. pii: candisc.1110.2021. [Epub ahead of print]
      Mosaic mutations in normal tissues can occur early in embryogenesis and be associated with hereditary cancer syndromes when affecting cancer susceptibility genes (CSGs). Their contribution to apparently sporadic cancers is currently unknown. Analysis of paired tumor/blood sequencing data of 35,310 cancer patients revealed 36 pathogenic mosaic variants affecting CSGs, most of which were not detected by prior clinical genetic testing. These CSG mosaic variants were consistently detected at varying variant allelic fractions in microdissected normal tissues (n=48) from distinct embryonic lineages in all individuals tested, indicating their early embryonic origin, likely prior to gastrulation, and likely asymmetrical propagation. Tumor-specific biallelic inactivation of the CSG affected by a mosaic variant was observed in 91.7% (33/36) of cases and tumors displayed the hallmark pathologic and/or genomic features of inactivation of the respective CSGs, establishing a causal link between CSG mosaic variants arising in early embryogenesis and the development of apparently sporadic cancers.
  33. EBioMedicine. 2021 Dec 18. pii: S2352-3964(21)00561-2. [Epub ahead of print]75 103767
      BACKGROUND: There is a critical need to better understand the mechanisms that drive local cell invasion and metastasis to develop new therapeutics targeting metastatic disease. Bioelectricity is an important mediator of cellular processes and changes in the resting membrane potential (RMP) are associated with increased cancer cell invasion. However, whether the RMP can be used to target invading cancer cells is unknown.METHODS: We employed both genetic and pharmacological manipulation of potassium channel activity and characterized the effects on breast cancer cell migration and invasion in vitro, and metastasis in an animal model of breast cancer.
    FINDINGS: Our data demonstrate that altering the RMP of triple-negative breast cancer (TNBC) cells by manipulating potassium channel expression increases in vitro invasion, in vivo tumour growth and metastasis, and is accompanied by changes in gene expression associated with cell adhesion.
    INTERPRETATION: We describe a novel mechanism for RMP-mediated cell migration involving cadherin-11 and the MAPK pathway. Importantly, we identify a new strategy to target metastatic TNBC in vivo by repurposing an FDA-approved potassium channel blocker. Our results demonstrate that bioelectricity regulates cancer cell invasion and metastasis which could lead to a new class of therapeutics for patients with metastatic disease.
    FUNDING: This work was supported by the National Institutes of Health (R00-CA207866 to M.J.O.), Tufts University (Start-up funds from the School of Engineering to M.J.O., Tufts Collaborates Award to M.J.O. and M.L.), Allen Discovery centre program (Paul G. Allen Frontiers Group (12,171) to M.L.), and Breast Cancer Alliance Young Investigator Grant to M.J.O, Laidlaw Scholar funding to D.S. M.L. also gratefully acknowledges support of the Barton Family Foundation.
    Keywords:  Cell adhesion; Cell invasion; Drug therapy; Ion channel; Migration