bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023–02–19
thirty papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Blocking muscle wasting via deletion of the muscle-specific E3 ubiquitin ligase MuRF1 impedes pancreatic tumor growth.
  2. Genomic Biomarkers Associated with Response to Induction Chemotherapy in Patients with Localized Pancreatic Ductal Adenocarcinoma.
  3. The outer mitochondrial membrane protein TMEM11 demarcates spatially restricted BNIP3/BNIP3L-mediated mitophagy.
  4. Kras mutation rate precisely orchestrates ductal derived pancreatic intraepithelial neoplasia and pancreatic cancer.
  5. Uncoupling Metastasis from Tumorigenesis.
  6. Lysosomal lipid peroxidation regulates tumor immunity.
  7. Spatially restricted tumour-associated and host-associated immune drivers correlate with the recurrence sites of pancreatic cancer.
  8. A timeline of tumour-associated macrophage biology.
  9. NKG2A blocks the anti-metastatic functions of natural killer cells.
  10. Stiff matrix induces exosome secretion to promote tumour growth.
  11. Mitochondrial metabolism in primary and metastatic human kidney cancers.
  12. Cytoskeletal association of ATP citrate lyase controls the mechanodynamics of macropinocytosis.
  13. Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer.
  14. SQSTM1 facilitates oocyte maturation through inducing ACLY degradation mediated by selective autophagy.
  15. The energetics of rapid cellular mechanotransduction.
  16. Dynamics of co-substrate pools can constrain and regulate metabolic fluxes.
  17. Tissue clearing and 3D reconstruction of digitized, serially sectioned slides provide novel insights into pancreatic cancer.
  18. Phase separation can regulate membrane curvature generation by bar-proteins.
  19. NADPH oxidase 1 in chronic pancreatitis-activated pancreatic stellate cells facilitates the progression of pancreatic cancer.
  20. Mechanoimmunological control of metastatic site preference.
  21. Predicting membrane orientational states of RAS and RAS-RAF based on the lipid environment using deep learning.
  22. Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma.
  23. Chemical potential measurements constrain models of cholesterol-phosphatidylcholine interactions.
  24. Pancreatic cancer metastasis: Adhesion and stiffness.
  25. Do cell membranes support or resist tension propagation?
  26. Tension-suppressed degradation of collagen controls tissue stiffness scaling with fibrillar collagen.
  27. Genetically Engineered Mouse Models Shine New Light on Decades-old Story of Trypsin in Pancreatitis.
  28. Characterization of integrin tension during chemotaxis of metastatic cancer cells in confinement.
  29. Quantifying organellar ultrastructure in cryo-electron tomography using a surface morphometrics pipeline.
  30. Editorial: Neoadjuvant treatment for resectable and borderline resectable pancreatic cancer.
  1. Res Sq. 2023 Feb 09. pii: rs.3.rs-2524562. [Epub ahead of print]
    Blocking muscle wasting via deletion of the muscle-specific E3 ubiquitin ligase MuRF1 impedes pancreatic tumor growth.
    Daria Neyroud, Orlando Laitano, Aneesha Dasgupta, Christopher Lopez, Rebecca Schmitt, Jessica Schneider, David Hammers, Lee Sweeney, Glenn Walter, Jason Doles, Sarah Judge, Andrew Judge.
      Cancer-induced muscle wasting reduces quality of life, complicates or precludes cancer treatments, and predicts early mortality. Herein, we investigated the requirement of the muscle-specific E3 ubiquitin ligase, MuRF1, for muscle wasting induced by pancreatic cancer. Murine pancreatic cancer (KPC) cells, or saline, were injected into the pancreas of WT and MuRF1-/- mice, and tissues analyzed throughout tumor progression. KPC tumors induced progressive wasting of skeletal muscle and systemic metabolic reprogramming in WT mice, but not MuRF1-/- mice. KPC tumors from MuRF1-/- mice also grew slower, and showed an accumulation of metabolites normally depleted by rapidly growing tumors. Mechanistically, MuRF1 was necessary for the KPC-induced increases in cytoskeletal and muscle contractile protein ubiquitination, and the depression of proteins that support protein synthesis. Together, these data demonstrate that MuRF1 is required for KPC-induced skeletal muscle wasting, whose deletion reprograms the systemic and tumor metabolome and delays tumor growth.
    DOI:  https://doi.org/10.21203/rs.3.rs-2524562/v1
  2. Clin Cancer Res. 2023 Feb 16. OF1-OF7
    Genomic Biomarkers Associated with Response to Induction Chemotherapy in Patients with Localized Pancreatic Ductal Adenocarcinoma.
    Brett L Ecker, Alice J Tao, Quisette P Janssen, Henry S Walch, Colin M Court, Vinod P Balachandran, Christopher H Crane, Michael I D'Angelica, Jeffrey A Drebin, T Peter Kingham, Kevin C Soares, Christine A Iacobuzio-Donahue, Efsevia Vakiani, Mithat Gonen, Eileen M O'Reilly, Anna M Varghese, William R Jarnagin, Alice C Wei.
       PURPOSE: There is increasing use of neoadjuvant chemotherapy in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers to guide therapy selection. We aimed to determine whether somatic genomic biomarkers predict response to induction FOLFIRINOX or gemcitabine/nab-paclitaxel.
    EXPERIMENTAL DESIGN: This single-institution cohort study included consecutive patients (N = 322) with localized PDAC (2011-2020) who received at least one cycle of FOLFIRINOX (N = 271) or gemcitabine/nab-paclitaxel (N = 51) as initial treatment. We assessed somatic alterations in four driver genes (KRAS, TP53, CDKN2A, and SMAD4) by targeted next-generation sequencing, and determined associations between these alterations and (1) rate of metastatic progression during induction chemotherapy, (2) surgical resection, and (3) complete/major pathologic response.
    RESULTS: The alteration rates in driver genes KRAS, TP53, CDKN2A, and SMAD4 were 87.0%, 65.5%, 26.7%, and 19.9%, respectively. For patients receiving first-line FOLFIRINOX, SMAD4 alterations were uniquely associated with metastatic progression (30.0% vs. 14.5%; P = 0.009) and decreased rate of surgical resection (37.1% vs. 66.7%; P < 0.001). For patients receiving induction gemcitabine/nab-paclitaxel, alterations in SMAD4 were not associated with metastatic progression (14.3% vs. 16.2%; P = 0.866) nor decreased rate of surgical resection (33.3% vs. 41.9%; P = 0.605). Major pathologic response was rare (6.3%) and not associated with type of chemotherapy regimen.
    CONCLUSIONS: SMAD4 alterations were associated with more frequent development of metastasis and lower probability of reaching surgical resection during neoadjuvant FOLFIRINOX but not gemcitabine/nab-paclitaxel. Confirmation in a larger, diverse patient cohort will be important before prospective evaluation of SMAD4 as a genomic biomarker to guide treatment selection.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-3089
  3. J Cell Biol. 2023 Apr 03. pii: e202204021. [Epub ahead of print]222(4):
    The outer mitochondrial membrane protein TMEM11 demarcates spatially restricted BNIP3/BNIP3L-mediated mitophagy.
    Mehmet Oguz Gok, Olivia M Connor, Xun Wang, Cameron J Menezes, Claire B Llamas, Prashant Mishra, Jonathan R Friedman.
      Mitochondria play critical roles in cellular metabolism and to maintain their integrity, they are regulated by several quality control pathways, including mitophagy. During BNIP3/BNIP3L-dependent receptor-mediated mitophagy, mitochondria are selectively targeted for degradation by the direct recruitment of the autophagy protein LC3. BNIP3 and/or BNIP3L are upregulated situationally, for example during hypoxia and developmentally during erythrocyte maturation. However, it is not well understood how they are spatially regulated within the mitochondrial network to locally trigger mitophagy. Here, we find that the poorly characterized mitochondrial protein TMEM11 forms a complex with BNIP3 and BNIP3L and co-enriches at sites of mitophagosome formation. We find that mitophagy is hyper-active in the absence of TMEM11 during both normoxia and hypoxia-mimetic conditions due to an increase in BNIP3/BNIP3L mitophagy sites, supporting a model that TMEM11 spatially restricts mitophagosome formation.
    DOI:  https://doi.org/10.1083/jcb.202204021
  4. Lab Invest. 2021 Feb;pii: S0023-6837(22)00308-7. [Epub ahead of print]101(2): 177-192
    Kras mutation rate precisely orchestrates ductal derived pancreatic intraepithelial neoplasia and pancreatic cancer.
    Kanchan Singh, Melissa Pruski, Rachael Bland, Mamoun Younes, Sushovan Guha, Nirav Thosani, Anirban Maitra, Brooks D Cash, Florencia McAllister, Craig D Logsdon, Jeffrey T Chang, Jennifer M Bailey-Lundberg.
      Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Despite the high prevalence of Kras mutations in pancreatic cancer patients, murine models expressing the oncogenic mutant Kras (Krasmut) in mature pancreatic cells develop PDAC at a low frequency. Independent of cell of origin, a second genetic hit (loss of tumor suppressor TP53 or PTEN) is important for development of PDAC in mice. We hypothesized ectopic expression and elevated levels of oncogenic mutant Kras would promote PanIN arising in pancreatic ducts. To test our hypothesis, the significance of elevating levels of K-Ras and Ras activity has been explored by expression of a CAG driven LGSL-KrasG12V allele (cKras) in pancreatic ducts, which promotes ectopic Kras expression. We predicted expression of cKras in pancreatic ducts would generate neoplasia and PDAC. To test our hypothesis, we employed tamoxifen dependent CreERT2 mediated recombination. Hnf1b:CreERT2;KrasG12V (cKrasHnf1b/+) mice received 1 (Low), 5 (Mod) or 10 (High) mg per 20 g body weight to recombine cKras in low (cKrasLow), moderate (cKrasMod), and high (cKrasHigh) percentages of pancreatic ducts. Our histologic analysis revealed poorly differentiated aggressive tumors in cKrasHigh mice. cKrasMod mice had grades of Pancreatic Intraepithelial Neoplasia (PanIN), recapitulating early and advanced PanIN observed in human PDAC. Proteomics analysis revealed significant differences in PTEN/AKT and MAPK pathways between wild type, cKrasLow, cKrasMod, and cKrasHigh mice. In conclusion, in this study, we provide evidence that ectopic expression of oncogenic mutant K-Ras in pancreatic ducts generates early and late PanIN as well as PDAC. This Ras rheostat model provides evidence that AKT signaling is an important early driver of invasive ductal derived PDAC. SUMMARY: In this study, the authors provide evidence that ectopic expression of oncogenic mutant Kras in pancreatic ducts generates early and late (PanIN) and pancreatic ductal adenocarcinoma (PDAC) . They characterized this Ras rheostat model which reveals elevated Kras mutation frequency and loss of PTEN are important drivers of PanIN and invasive ductal derived PDAC.
    DOI:  https://doi.org/10.1038/s41374-020-00490-5
  5. N Engl J Med. 2023 Feb 16. 388(7): 657-659
    Uncoupling Metastasis from Tumorigenesis.
    Karuna Ganesh.
      
    DOI:  https://doi.org/10.1056/NEJMcibr2213497
  6. J Clin Invest. 2023 Feb 16. pii: e164596. [Epub ahead of print]
    Lysosomal lipid peroxidation regulates tumor immunity.
    Monika Bhardwaj, Jennifer J Lee, Amanda M Versace, Sandra L Harper, Aaron R Goldman, Mary Ann S Crissey, Vaibhav Jain, Mahendra Pal Singh, Megane Vernon, Andrew E Aplin, Seokwoo Lee, Masao Morita, Jeffrey D Winkler, Qin Liu, David W Speicher, Ravi K Amaravadi.
      Lysosomal inhibition elicited by palmitoyl protein transferase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were not required to achieve the cytotoxic effect of DC661. Inhibition of cathepsins, or iron or calcium chelation, did not rescue DC661-induced cytotoxicity. PPT1 inhibition induced lysosomal lipid peroxidation (LLP), which led to lysosomal membrane permeabilization and cell death that could be reversed by the antioxidant N-acetylcysteine (NAC), but not by other lipid peroxidation antioxidants. The lysosomal cysteine transporter MFSD12, was required for intralysosomal transport of NAC and rescue of LLP. PPT1 inhibition produced cell-intrinsic immunogenicity with surface expression of calreticulin that could only be reversed with NAC. DC661-treated cells primed naïve T cells, and enhanced T cell-mediated toxicity. Mice vaccinated with DC661-treated cells, engendered adaptive immunity and tumor rejection in "immune hot" tumors but not in "immune cold" tumors. These findings demonstrate LLP drives lysosomal cell death, a unique immunogenic form of cell death, pointing the way to rational combinations of immunotherapy and lysosomal inhibition that can be tested in clinical trials.
    Keywords:  Cancer; Cellular immune response; Lysosomes; Oncology
    DOI:  https://doi.org/10.1172/JCI164596
  7. Gut. 2023 Feb 15. pii: gutjnl-2022-329371. [Epub ahead of print]
    Spatially restricted tumour-associated and host-associated immune drivers correlate with the recurrence sites of pancreatic cancer.
    Eva Karamitopoulou, Anna Silvia Wenning, Animesh Acharjee, Inti Zlobec, Pauline Aeschbacher, Aurel Perren, Beat Gloor.
       OBJECTIVE: Most patients with pancreatic ductal adenocarcinoma (PDAC) will experience recurrence after resection. Here, we investigate spatially organised immune determinants of PDAC recurrence.
    DESIGN: PDACs (n=284; discovery cohort) were classified according to recurrence site as liver (n=93/33%), lung (n=49/17%), local (n=31/11%), peritoneal (n=38/13%) and no-recurrence (n=73/26%). Spatial compartments were identified by fluorescent imaging as: pancytokeratin (PanCK)+CD45- (tumour cells); CD45+PanCK- (leucocytes) and PanCK-CD45- (stromal cells), followed by transcriptomic (72 genes) and proteomic analysis (51 proteins) for immune pathway targets. Results from next-generation sequencing (n=194) were integrated. Finally, 10 tumours from each group underwent immunophenotypic analysis by multiplex immunofluorescence. A validation cohort (n=109) was examined in parallel.
    RESULTS: No-recurrent PDACs show high immunogenicity, adaptive immune responses and are rich in pro-inflammatory chemokines, granzyme B and alpha-smooth muscle actin+ fibroblasts. PDACs with liver and/or peritoneal recurrences display low immunogenicity, stemness phenotype and innate immune responses, whereas those with peritoneal metastases are additionally rich in FAP+ fibroblasts. PDACs with local and/or lung recurrences display interferon-gamma signalling and mixed adaptive and innate immune responses, but with different leading immune cell population. Tumours with local recurrences overexpress dendritic cell markers whereas those with lung recurrences neutrophilic markers. Except the exclusive presence of RNF43 mutations in the no-recurrence group, no genetic differences were seen. The no-recurrence group exhibited the best, whereas liver and peritoneal recurrences the poorest prognosis.
    CONCLUSIONS: Our findings demonstrate distinct inflammatory/stromal responses in each recurrence group, which might affect dissemination patterns and patient outcomes. These findings may help to inform personalised adjuvant/neoadjuvant and surveillance strategies in PDAC, including immunotherapeutic modalities.
    Keywords:  cancer immunobiology; immune response; immunohistopathology; pancreatic cancer
    DOI:  https://doi.org/10.1136/gutjnl-2022-329371
  8. Nat Rev Cancer. 2023 Feb 15.
    A timeline of tumour-associated macrophage biology.
    Luca Cassetta, Jeffrey W Pollard.
      Tumour progression is modulated by the local microenvironment. This environment is populated by many immune cells, of which macrophages are among the most abundant. Clinical correlative data and a plethora of preclinical studies in mouse models of cancers have shown that tumour-associated macrophages (TAMs) play a cancer-promoting role. Within the primary tumour, TAMs promote tumour cell invasion and intravasation and tumour stem cell viability and induce angiogenesis. At the metastatic site, metastasis-associated macrophages promote extravasation, tumour cell survival and persistent growth, as well as maintain tumour cell dormancy in some contexts. In both the primary and metastatic sites, TAMs are suppressive to the activities of cytotoxic T and natural killer cells that have the potential to eradicate tumours. Such activities suggest that TAMs will be a major target for therapeutic intervention. In this Perspective article, we chronologically explore the evolution of our understanding of TAM biology put into the context of major enabling advances in macrophage biology.
    DOI:  https://doi.org/10.1038/s41568-022-00547-1
  9. Cancer Cell. 2023 Feb 13. pii: S1535-6108(23)00008-9. [Epub ahead of print]41(2): 232-234
    NKG2A blocks the anti-metastatic functions of natural killer cells.
    Florent Carrette, Eric Vivier.
      Pancreatic ductal adenocarcinoma (PDAC)-derived liver metastasis represents a major unmet medical need. Liu et al. show that circulating tumor cells (CTCs) from the hepatic portal vein (HPV), and not from primary or metastatic sites, are protected from natural killer (NK) cells through the NKG2A/HLA-E axis. Interfering with this pathway unleashes NK cells and prevents PDAC metastasis.
    DOI:  https://doi.org/10.1016/j.ccell.2023.01.008
  10. Nat Cell Biol. 2023 Feb 16.
    Stiff matrix induces exosome secretion to promote tumour growth.
    Bin Wu, Di-Ao Liu, Lei Guan, Phyoe Kyawe Myint, LiKang Chin, Hien Dang, Ye Xu, Jinqi Ren, Ting Li, Ziyan Yu, Sophie Jabban, Gordon B Mills, Jonathan Nukpezah, Youhai H Chen, Emma E Furth, Phyllis A Gimotty, Rebecca G Wells, Valerie M Weaver, Ravi Radhakrishnan, Xin Wei Wang, Wei Guo.
      Tissue fibrosis and extracellular matrix (ECM) stiffening promote tumour progression. The mechanisms by which ECM regulates its contacting cells have been extensively studied. However, how stiffness influences intercellular communications in the microenvironment for tumour progression remains unknown. Here we report that stiff ECM stimulates the release of exosomes from cancer cells. We delineate a molecular pathway that links stiff ECM to activation of Akt, which in turn promotes GTP loading to Rab8 that drives exosome secretion. We further show that exosomes generated from cells grown on stiff ECM effectively promote tumour growth. Proteomic analysis revealed that the Notch signalling pathway is activated in cells treated with exosomes derived from tumour cells grown on stiff ECM, consistent with our gene expression analysis of liver tissues from patients. Our study reveals a molecular mechanism that regulates exosome secretion and provides insight into how mechanical properties of the ECM control the tumour microenvironment for tumour growth.
    DOI:  https://doi.org/10.1038/s41556-023-01092-1
  11. bioRxiv. 2023 Feb 07. pii: 2023.02.06.527285. [Epub ahead of print]
    Mitochondrial metabolism in primary and metastatic human kidney cancers.
    Divya Bezwada, Nicholas P Lesner, Bailey Brooks, Hieu S Vu, Zheng Wu, Ling Cai, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, McKenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Vitaly Margulis, Ralph J DeBerardinis.
      Most kidney cancers display evidence of metabolic dysfunction 1â€"4 but how this relates to cancer progression in humans is unknown. We used a multidisciplinary approach to infuse 13 C-labeled nutrients during surgical tumour resection in over 70 patients with kidney cancer. Labeling from [U- 13 C]glucose varies across cancer subtypes, indicating that the kidney environment alone cannot account for all metabolic reprogramming in these tumours. Compared to the adjacent kidney, clear cell renal cell carcinomas (ccRCC) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in organotypic slices cultured ex vivo, indicating that suppressed labeling is tissue intrinsic. Infusions of [1,2- 13 C]acetate and [U- 13 C]glutamine in patients, coupled with respiratory flux of mitochondria isolated from kidney and tumour tissue, reveal primary defects in mitochondrial function in human ccRCC. However, ccRCC metastases unexpectedly have enhanced labeling of TCA cycle intermediates compared to primary ccRCCs, indicating a divergent metabolic program during ccRCC metastasis in patients. In mice, stimulating respiration in ccRCC cells is sufficient to promote metastatic colonization. Altogether, these findings indicate that metabolic properties evolve during human kidney cancer progression, and suggest that mitochondrial respiration may be limiting for ccRCC metastasis but not for ccRCC growth at the site of origin.
    DOI:  https://doi.org/10.1101/2023.02.06.527285
  12. Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2213272120
    Cytoskeletal association of ATP citrate lyase controls the mechanodynamics of macropinocytosis.
    Joseph Puccini, Jia Wei, Liang Tong, Dafna Bar-Sagi.
      Macropinocytosis is an actin-dependent mode of nonselective endocytosis that mediates the uptake of extracellular fluid-phase cargoes. It is now well recognized that tumor cells exploit macropinocytosis to internalize macromolecules that can be catabolized and used to support cell growth and proliferation under nutrient-limiting conditions. Therefore, the identification of molecular mechanisms that control macropinocytosis is fundamental to the understanding of the metabolic adaptive landscape of tumor cells. Here, we report that the acetyl-CoA-producing enzyme, ATP citrate lyase (ACLY), is a key regulator of macropinocytosis and describes a heretofore-unappreciated association of ACLY with the actin cytoskeleton. The cytoskeletal tethering of ACLY is required for the spatially defined acetylation of heterodimeric actin capping protein, which we identify as an essential mediator of the actin remodeling events that drive membrane ruffling and macropinocytosis. Furthermore, we identify a requirement for mitochondrial-derived citrate, an ACLY substrate, for macropinocytosis, and show that mitochondria traffic to cell periphery regions juxtaposed to plasma membrane ruffles. Collectively, these findings establish a mode of metabolite compartmentalization that supports the spatiotemporal modulation of membrane-cytoskeletal interactions required for macropinocytosis by coupling regional acetyl-CoA availability with dynamic protein acetylation.
    Keywords:  actin cytoskeleton; macropinocytosis; membrane ruffling
    DOI:  https://doi.org/10.1073/pnas.2213272120
  13. Br J Cancer. 2023 Feb 13.
    Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer.
    Kumiko Umemoto, Yu Sunakawa, Makoto Ueno, Masayuki Furukawa, Nobumasa Mizuno, Kentaro Sudo, Yasuyuki Kawamoto, Takeshi Kajiwara, Koushiro Ohtsubo, Naohiro Okano, Nobuhisa Matsuhashi, Shinji Itoh, Toshihiko Matsumoto, Satoshi Shimizu, Toru Otsuru, Hiroko Hasegawa, Hiroyuki Okuyama, Hideko Ohama, Toshikazu Moriwaki, Takashi Ohta, Justin I Odegaard, Yoshiaki Nakamura, Hideaki Bando, Takayuki Yoshino, Masafumi Ikeda, Chigusa Morizane.
       BACKGROUND: Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC.
    METHODS: This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment.
    RESULTS: In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively).
    CONCLUSION: The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.
    DOI:  https://doi.org/10.1038/s41416-023-02189-y
  14. Cell Cycle. 2023 Feb 14. 1-3
    SQSTM1 facilitates oocyte maturation through inducing ACLY degradation mediated by selective autophagy.
    Heide Schatten.
      Selective autophagy specifically eliminates certain intracellular substrates through the autophagy pathway. Organelles and aggregation-prone proteins can be degraded through the autophagy receptor protein SQSTM1/p62, which renders them a promising therapeutic approach against infertility. He et al. demonstrate that blocking of autophagy in cumulus granulosa cells can directly attenuate citrate levels and in turn affect oocyte maturation quality. Further findings show that SQSTM1 connects K63-polyubiquitinated ACLY (ATP citrate lyase) during the process of selective autophagic degradation, which further compromises the homeostasis of citrate. Therefore, the quality of oocyte meiotic maturation can be evaluated by the levels of selective autophagy in cumulus granulosa cells.
    Keywords:  ACLY; Sqstm1/P62; citrate; meiotic resumption; selective autophagy
    DOI:  https://doi.org/10.1080/15384101.2023.2176673
  15. Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2215747120
    The energetics of rapid cellular mechanotransduction.
    Michael N Young, Michael J Sindoni, Amanda H Lewis, Stefan Zauscher, Jörg Grandl.
      Cells throughout the human body detect mechanical forces. While it is known that the rapid (millisecond) detection of mechanical forces is mediated by force-gated ion channels, a detailed quantitative understanding of cells as sensors of mechanical energy is still lacking. Here, we combine atomic force microscopy with patch-clamp electrophysiology to determine the physical limits of cells expressing the force-gated ion channels (FGICs) Piezo1, Piezo2, TREK1, and TRAAK. We find that, depending on the ion channel expressed, cells can function either as proportional or nonlinear transducers of mechanical energy and detect mechanical energies as little as ~100 fJ, with a resolution of up to ~1 fJ. These specific energetic values depend on cell size, channel density, and cytoskeletal architecture. We also make the surprising discovery that cells can transduce forces either nearly instantaneously (<1 ms) or with a substantial time delay (~10 ms). Using a chimeric experimental approach and simulations, we show how such delays can emerge from channel-intrinsic properties and the slow diffusion of tension in the membrane. Overall, our experiments reveal the capabilities and limits of cellular mechanosensing and provide insights into molecular mechanisms that different cell types may employ to specialize for their distinct physiological roles.
    Keywords:  force-gated ion channel; mechanotransduction; mechanotransmission
    DOI:  https://doi.org/10.1073/pnas.2215747120
  16. Elife. 2023 Feb 17. pii: e84379. [Epub ahead of print]12
    Dynamics of co-substrate pools can constrain and regulate metabolic fluxes.
    Robert West, Hadrien Delattre, Elad Noor, Elisenda Feliu, Orkun Soyer.
      Cycling of co-substrates, whereby a metabolite is converted among alternate forms via different reactions, is ubiquitous in metabolism. Several cycled co-substrates are well known as energy and electron carriers (e.g. ATP and NAD(P)H), but there are also other metabolites that act as cycled co-substrates in different parts of central metabolism. Here, we develop a mathematical framework to analyse the effect of co-substrate cycling on metabolic flux. In the cases of a single reaction and linear pathways, we find that co-substrate cycling imposes an additional flux limit on a reaction, distinct to the limit imposed by the kinetics of the primary enzyme catalysing that reaction. Using analytical methods, we show that this additional limit is a function of the total pool size and turnover rate of the cycled co-substrate. Expanding from this insight and using simulations, we show that regulation of these two parameters can allow regulation of flux dynamics in branched and coupled pathways. To support these theoretical insights, we analysed existing flux measurements and enzyme levels from the central carbon metabolism and identified several reactions that could be limited by the dynamics of co-substrate cycling. We discuss how the limitations imposed by co-substrate cycling provide experimentally testable hypotheses on specific metabolic phenotypes. We conclude that measuring and controlling co-substrate dynamics is crucial for understanding and engineering metabolic fluxes in cells.
    Keywords:  E. coli; computational biology; systems biology
    DOI:  https://doi.org/10.7554/eLife.84379
  17. Med (N Y). 2023 Feb 10. pii: S2666-6340(22)00490-1. [Epub ahead of print]4(2): 75-91
    Tissue clearing and 3D reconstruction of digitized, serially sectioned slides provide novel insights into pancreatic cancer.
    Ashley L Kiemen, Alexander Ioannis Damanakis, Alicia M Braxton, Jin He, Daniel Laheru, Elliot K Fishman, Patrick Chames, Cristina Almagro Pérez, Pei-Hsun Wu, Denis Wirtz, Laura D Wood, Ralph H Hruban.
      Pancreatic cancer is currently the third leading cause of cancer death in the United States. The clinical hallmarks of this disease include abdominal pain that radiates to the back, the presence of a hypoenhancing intrapancreatic lesion on imaging, and widespread liver metastases. Technologies such as tissue clearing and three-dimensional (3D) reconstruction of digitized serially sectioned hematoxylin and eosin-stained slides can be used to visualize large (up to 2- to 3-centimeter cube) tissues at cellular resolution. When applied to human pancreatic cancers, these 3D visualization techniques have provided novel insights into the basis of a number of the clinical characteristics of this disease. Here, we describe the clinical features of pancreatic cancer, review techniques for clearing and the 3D reconstruction of digitized microscope slides, and provide examples that illustrate how 3D visualization of human pancreatic cancer at the microscopic level has revealed features not apparent in 2D microscopy and, in so doing, has closed the gap between bench and bedside. Compared with animal models and 2D microscopy, studies of human tissues in 3D can reveal the difference between what can happen and what does happen in human cancers.
    Keywords:  CODA; artificial intelligence; clearing; digital pathology; machine learning; pancreatic cancer; three dimensions
    DOI:  https://doi.org/10.1016/j.medj.2022.11.009
  18. Biophys J. 2023 Feb 10. pii: S0006-3495(22)01300-5. [Epub ahead of print]122(3S1): 30a
    Phase separation can regulate membrane curvature generation by bar-proteins.
    Samsuzzoha Mondal, Karthik Narayan, Tobias Baumgart.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.384
  19. Am J Cancer Res. 2023 ;13(1): 118-142
    NADPH oxidase 1 in chronic pancreatitis-activated pancreatic stellate cells facilitates the progression of pancreatic cancer.
    Ananya Chakraborty, Bithika Halder, Souravi Mondal, Amanda Barrett, Wenbo Zhi, Gabor Csanyi, Maria E Sabbatini.
      Patients suffering from chronic pancreatitis (CP) have a higher risk of pancreatic ductal adenocarcinoma (PDAC) compared to the general population. For instance, the presence of an activated pancreatic stellate cell (PaSC)-rich stroma in CP has facilitated the progression of non-invasive pancreatic intraepithelial neoplasia (PanIN) lesions to invasive PDAC. We have previously found that in a mouse model of CP, NADPH oxidase 1 (Nox1) in activated PaSCs forms fibrotic tissue and up-regulates both matrix metalloproteinase (MMP) 9 and the transcription factor Twist1. Yet, the role and mechanism of Nox1 in activated PaSCs from mice with CP (CP-activated PaSCs) in the progression of PDAC is unknown. For that, we tested the ability of Nox1 in CP-activated PaSCs to facilitate the growth of pancreatic cancer cells, and the mechanisms involved in these effects by identifying proteins in the secretome of CP-activated PaSCs whose production were Nox1-dependent. We found that, in vitro, Nox1 evoked a pro-invasive and cancer-promoting phenotype in CP-activated PaSCs via Twist1/MMP-9 expression, causing changes in the extracellular matrix composition. In vivo, Nox1 in CP-activated PaSCs facilitated tumor growth and stromal expansion. Using mass spectrometry, we identified proteins protecting from endoplasmic reticulum, oxidative and metabolic stresses in the secretome of CP-activated PaSCs whose production was Nox1-dependent, including peroxiredoxins (Prdx1 and Prdx4), and thioredoxin reductase 1. In conclusion, inhibiting the Nox1 signaling in activated PaSCs from patients with CP at early stages can reduce the reorganization of extracellular matrix, and the protection of neoplastic cells from cellular stresses, ameliorating the progression of PDAC.
    Keywords:  MMP-9; NADPH oxidase 1; Twist1; extracellular matrix; pancreatic stellate cells; peroxiredoxin; thioredoxin reductase 1
  20. Biophys J. 2023 Feb 10. pii: S0006-3495(22)03744-4. [Epub ahead of print]122(3S1): 533a-534a
    Mechanoimmunological control of metastatic site preference.
    Yassmin Elbanna, Maria Tello-Lafoz, Ye Zhang, Elisa E Sanchez, Scott Manalis, Morgan Huse.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.2828
  21. Biophys J. 2023 Feb 10. pii: S0006-3495(22)03613-X. [Epub ahead of print]122(3S1): 506a
    Predicting membrane orientational states of RAS and RAS-RAF based on the lipid environment using deep learning.
    Fikret Aydin, Konstantia Georgouli, Gautham Dharuman, James N Glosli, Timothy S Carpenter, Felice C Lightstone, Helgi Ingolfsson, Peer-Timo Bremer, Harsh Bhatia.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.2697
  22. Nat Commun. 2023 Feb 15. 14(1): 861
    Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma.
    Qing Li, Xiao-Xin Zhang, Li-Peng Hu, Bo Ni, Dong-Xue Li, Xu Wang, Shu-Heng Jiang, Hui Li, Min-Wei Yang, Yong-Sheng Jiang, Chun-Jie Xu, Xue-Li Zhang, Yan-Li Zhang, Pei-Qi Huang, Qin Yang, Yang Zhou, Jian-Ren Gu, Gary Gui-Shan Xiao, Yong-Wei Sun, Jun Li, Zhi-Gang Zhang.
      To explore the mechanism of coadaptation and the potential drivers of pancreatic ductal adenocarcinoma (PDAC) metastasis to the liver, we study key molecules involved in this process and their translational value. Premetastatic niche (PMN) and macrometastatic niche (MMN) formation in a mouse model is observed via CT combined with 3D organ reconstruction bioluminescence imaging, and then we screen slit guidance ligand 2 (SLIT2) and its receptor roundabout guidance receptor 1 (ROBO1) as important factors. After we confirm the expression and distribution of SLIT2 and ROBO1 in samples from PDAC patients and several mouse models, we discover that SLIT2-ROBO1-mediated coadaptation facilitated the implantation and outgrowth of PDAC disseminated tumour cells (DTCs) in the liver. We also demonstrate the dependence receptor (DR) characteristics of ROBO1 in a follow-up mechanistic study. A neutralizing antibody targeting ROBO1 significantly attenuate liver metastasis of PDAC by preventing the coadaptation effect. Thus, we demonstrate that coadaptation is supported by the DR characteristics in the PMN and MMN.
    DOI:  https://doi.org/10.1038/s41467-023-36521-0
  23. Biophys J. 2023 Feb 11. pii: S0006-3495(23)00101-7. [Epub ahead of print]
    Chemical potential measurements constrain models of cholesterol-phosphatidylcholine interactions.
    Thomas R Shaw, Kathleen Wisser, Taylor A Schaffner, Anna D Gaffney, Benjamin B Machta, Sarah L Veatch.
      Bilayer membranes composed of cholesterol and phospholipids exhibit diverse forms of non-ideal mixing. In particular, many previous studies document macroscopic liquid-liquid phase separation as well as nanometer-scale heterogeneity in membranes of phosphatidylcholine (PC) lipids and cholesterol. Here, we present experimental measurements of cholesterol chemical potential (μc) in binary membranes containing dioleoyl PC (DOPC), 1-palmitoyl-2-oleoyl PC (POPC), or dipalmitoyl PC (DPPC), and in ternary membranes of DOPC and DPPC, referenced to crystalline cholesterol. μc is the thermodynamic quantity that dictates the availability of cholesterol to bind other factors, and notably must be equal between coexisting phases of a phase-separated mixture. It is simply related to concentration under conditions of ideal mixing, but is far from ideal for the majority of lipid mixtures investigated here. Measurements of μc can vary with phospholipid composition by 1.5 kBT at constant cholesterol mole-fraction implying a more than five-fold change in its availability for binding receptors and other reactions. Experimental measurements are fit to thermodynamic models including cholesterol-DPPC complexes or pairwise interactions between lipid species to provide intuition about the magnitude of interactions. These findings reinforce that μc depends on membrane composition overall, suggesting avenues for cells to alter the availability of cholesterol without varying cholesterol concentration.
    DOI:  https://doi.org/10.1016/j.bpj.2023.02.009
  24. Biophys J. 2023 Feb 10. pii: S0006-3495(22)03746-8. [Epub ahead of print]122(3S1): 534a
    Pancreatic cancer metastasis: Adhesion and stiffness.
    Shruti G Kulkarni, Manfred Radmacher, Malgorzata Lekka.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.2830
  25. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02457-2. [Epub ahead of print]122(3S1): 269a
    Do cell membranes support or resist tension propagation?
    Henry De Belly, Shannon Yan, Hudson Borja da Rocha, Sacha Ichbiah, Jason P Town, Hervé Turlier, Carlos Bustamante, Orion Weiner.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1541
  26. Biophys J. 2023 Feb 10. pii: S0006-3495(22)01586-7. [Epub ahead of print]122(3S1): 87a
    Tension-suppressed degradation of collagen controls tissue stiffness scaling with fibrillar collagen.
    Karanvir Saini, Sangkyun Cho, Manu Tewari, Abdelaziz Jalil, Mai Wang, Manasvita Vashisth, Alex Kasznel, Kazuhiro Yamamoto, David M Chenoweth, Dennis E Discher.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.670
  27. Gastroenterology. 2023 Feb 10. pii: S0016-5085(23)00115-4. [Epub ahead of print]
    Genetically Engineered Mouse Models Shine New Light on Decades-old Story of Trypsin in Pancreatitis.
    Bomi Lee, Sohail Z Husain, Ilya Gukovsky.
      
    DOI:  https://doi.org/10.1053/j.gastro.2023.02.002
  28. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02432-8. [Epub ahead of print]122(3S1): 264a
    Characterization of integrin tension during chemotaxis of metastatic cancer cells in confinement.
    Byoung Choul Kim.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1516
  29. J Cell Biol. 2023 Apr 03. pii: e202204093. [Epub ahead of print]222(4):
    Quantifying organellar ultrastructure in cryo-electron tomography using a surface morphometrics pipeline.
    Benjamin A Barad, Michaela Medina, Daniel Fuentes, R Luke Wiseman, Danielle A Grotjahn.
      Cellular cryo-electron tomography (cryo-ET) enables three-dimensional reconstructions of organelles in their native cellular environment at subnanometer resolution. However, quantifying ultrastructural features of pleomorphic organelles in three dimensions is challenging, as is defining the significance of observed changes induced by specific cellular perturbations. To address this challenge, we established a semiautomated workflow to segment organellar membranes and reconstruct their underlying surface geometry in cryo-ET. To complement this workflow, we developed an open-source suite of ultrastructural quantifications, integrated into a single pipeline called the surface morphometrics pipeline. This pipeline enables rapid modeling of complex membrane structures and allows detailed mapping of inter- and intramembrane spacing, curvedness, and orientation onto reconstructed membrane meshes, highlighting subtle organellar features that are challenging to detect in three dimensions and allowing for statistical comparison across many organelles. To demonstrate the advantages of this approach, we combine cryo-ET with cryo-fluorescence microscopy to correlate bulk mitochondrial network morphology (i.e., elongated versus fragmented) with membrane ultrastructure of individual mitochondria in the presence and absence of endoplasmic reticulum (ER) stress. Using our pipeline, we demonstrate ER stress promotes adaptive remodeling of ultrastructural features of mitochondria including spacing between the inner and outer membranes, local curvedness of the inner membrane, and spacing between mitochondrial cristae. We show that differences in membrane ultrastructure correlate to mitochondrial network morphologies, suggesting that these two remodeling events are coupled. Our pipeline offers opportunities for quantifying changes in membrane ultrastructure on a single-cell level using cryo-ET, opening new opportunities to define changes in ultrastructural features induced by diverse types of cellular perturbations.
    DOI:  https://doi.org/10.1083/jcb.202204093
  30. Front Oncol. 2023 ;13 1138587
    Editorial: Neoadjuvant treatment for resectable and borderline resectable pancreatic cancer.
    Marco Massani, Tommaso Stecca.
      
    Keywords:  Neoadjuvant chemo(radio)therapy; borderline resectable pancreatic cancer (BRPC); locally advanced pancreatic cancer (LAPC); lymphnode metastasis; pancreatic cancer
    DOI:  https://doi.org/10.3389/fonc.2023.1138587
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