bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022–10–09
25 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome.
  2. Calcium transients on the ER surface trigger liquid-liquid phase separation of FIP200 to specify autophagosome initiation sites.
  3. Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex.
  4. Proportion of unresectable pancreatic cancer specimens obtained by endoscopic ultrasound-guided tissue acquisition meeting the OncoGuide™ NCC Oncopanel System analysis suitability criteria: a single-arm, phase II clinical trial.
  5. Cancer fitness genes: emerging therapeutic targets for metastasis.
  6. Mesoscale structure-function relationships in mitochondrial transcriptional condensates.
  7. Charting metastasis.
  8. Orchestration of Collective Migration and Metastasis by Tumor Cell Clusters.
  9. Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability.
  10. Whole-slide imaging and a Fiji-based image analysis workflow of immunohistochemistry staining of pancreatic islets.
  11. Starving cancer into submission by activating BAT.
  12. Focus on diet and exercise.
  13. Multiscale profiling of protease activity in cancer.
  14. Two independent respiratory chains adapt OXPHOS performance to glycolytic switch.
  15. Subcapsular sinus macrophages promote melanoma metastasis to the sentinel lymph nodes via an IL-1α-STAT3 axis.
  16. The multifaceted role of micronuclei in tumour progression: A whole organism perspective.
  17. Interplay between substrate rigidity and tissue fluidity regulates cell monolayer spreading.
  18. Sequencing single cells without killing.
  19. Cancer and aging: A call to action.
  20. Cancer metastasis chemoprevention prevents circulating tumour cells from germination.
  21. RPPA SPACE: An R package for normalization and quantitation of Reverse-Phase Protein Array (RPPA) data.
  22. TumorMet: A repository of tumor metabolic networks derived from context-specific Genome-Scale Metabolic Models.
  23. Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer.
  24. Telomere Attrition in Intraductal Papillary Mucinous Neoplasms of the Pancreas Associated With Carcinogenesis and Aging.
  25. Lipid Expansion Microscopy.
  1. Nature. 2022 Oct 05.
    Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome.
    Hua Su, Fei Yang, Rao Fu, Brittney Trinh, Nina Sun, Junlai Liu, Avi Kumar, Jacopo Baglieri, Jeremy Siruno, Michelle Le, Yuhan Li, Stephen Dozier, Ajay Nair, Aveline Filliol, Nachanok Sinchai, Sara Brin Rosenthal, Jennifer Santini, Christian M Metallo, Anthony Molina, Robert F Schwabe, Andrew M Lowy, David Brenner, Beicheng Sun, Michael Karin.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses and spreads by metastasis to the liver1. Cancer-associated fibroblasts, the extracellular matrix and type I collagen (Col I) support2,3 or restrain the progression of PDAC and may impede blood supply and nutrient availability4. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation, remain poorly understood. Here we show that matrix-metalloprotease-cleaved Col I (cCol I) and intact Col I (iCol I) exert opposing effects on PDAC bioenergetics, macropinocytosis, tumour growth and metastasis. Whereas cCol I activates discoidin domain receptor 1 (DDR1)-NF-κB-p62-NRF2 signalling to promote the growth of PDAC, iCol I triggers the degradation of DDR1 and restrains the growth of PDAC. Patients whose tumours are enriched for iCol I and express low levels of DDR1 and NRF2 have improved median survival compared to those whose tumours have high levels of cCol I, DDR1 and NRF2. Inhibition of the DDR1-stimulated expression of NF-κB or mitochondrial biogenesis blocks tumorigenesis in wild-type mice, but not in mice that express MMP-resistant Col I. The diverse effects of the tumour stroma on the growth and metastasis of PDAC and on the survival of patients are mediated through the Col I-DDR1-NF-κB-NRF2 mitochondrial biogenesis pathway, and targeting components of this pathway could provide therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41586-022-05169-z
  2. Cell. 2022 Sep 30. pii: S0092-8674(22)01123-0. [Epub ahead of print]
    Calcium transients on the ER surface trigger liquid-liquid phase separation of FIP200 to specify autophagosome initiation sites.
    Qiaoxia Zheng, Yong Chen, Di Chen, Hongyu Zhao, Yun Feng, Quan Meng, Yan Zhao, Hong Zhang.
      The mechanism that initiates autophagosome formation on the ER in multicellular organisms is elusive. Here, we showed that autophagy stimuli trigger Ca2+ transients on the outer surface of the ER membrane, whose amplitude, frequency, and duration are controlled by the metazoan-specific ER transmembrane autophagy protein EPG-4/EI24. Persistent Ca2+ transients/oscillations on the cytosolic ER surface in EI24-depleted cells cause accumulation of FIP200 autophagosome initiation complexes on the ER. This defect is suppressed by attenuating ER Ca2+ transients. Multi-modal SIM analysis revealed that Ca2+ transients on the ER trigger the formation of dynamic and fusion-prone liquid-like FIP200 puncta. Starvation-induced Ca2+ transients on lysosomes also induce FIP200 puncta that further move to the ER. Multiple FIP200 puncta on the ER, whose association depends on the ER proteins VAPA/B and ATL2/3, assemble into autophagosome formation sites. Thus, Ca2+ transients are crucial for triggering phase separation of FIP200 to specify autophagosome initiation sites in metazoans.
    Keywords:  ATG9; Ca(2+) transient; EI24; ER; FIP200; autophagosome formation; liquid-liquid phase separation; lysosome
    DOI:  https://doi.org/10.1016/j.cell.2022.09.001
  3. Mol Cell. 2022 Oct 06. pii: S1097-2765(22)00895-4. [Epub ahead of print]82(19): 3661-3676.e8
    Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex.
    Chen-Wei Tsai, Madison X Rodriguez, Anna M Van Keuren, Charles B Phillips, Hannah M Shushunov, Jessica E Lee, Anastacia M Garcia, Amrut V Ambardekar, Joseph C Cleveland, Julie A Reisz, Catherine Proenza, Kathryn C Chatfield, Ming-Feng Tsai.
      Mitochondrial Ca2+ uptake, mediated by the mitochondrial Ca2+ uniporter, regulates oxidative phosphorylation, apoptosis, and intracellular Ca2+ signaling. Previous studies suggest that non-neuronal uniporters are exclusively regulated by a MICU1-MICU2 heterodimer. Here, we show that skeletal-muscle and kidney uniporters also complex with a MICU1-MICU1 homodimer and that human/mouse cardiac uniporters are largely devoid of MICUs. Cells employ protein-importation machineries to fine-tune the relative abundance of MICU1 homo- and heterodimers and utilize a conserved MICU intersubunit disulfide to protect properly assembled dimers from proteolysis by YME1L1. Using the MICU1 homodimer or removing MICU1 allows mitochondria to more readily take up Ca2+ so that cells can produce more ATP in response to intracellular Ca2+ transients. However, the trade-off is elevated ROS, impaired basal metabolism, and higher susceptibility to death. These results provide mechanistic insights into how tissues can manipulate mitochondrial Ca2+ uptake properties to support their unique physiological functions.
    Keywords:  calcium channels; cardiac pathophysiology; cellular metabolism; intracellular calcium signaling; membrane-transport mechanisms; mitochondrial physiology; mitochondrial proteases; organellar channels; protein complexes
    DOI:  https://doi.org/10.1016/j.molcel.2022.09.006
  4. J Gastroenterol. 2022 Oct 03.
    Proportion of unresectable pancreatic cancer specimens obtained by endoscopic ultrasound-guided tissue acquisition meeting the OncoGuide™ NCC Oncopanel System analysis suitability criteria: a single-arm, phase II clinical trial.
    Yuya Hisada, Susumu Hijioka, Go Ikeda, Kosuke Maehara, Taiki Hashimoto, Hidetoshi Kitamura, Shota Harai, Motohiro Yoshinari, Yuki Kawasaki, Yumi Murashima, Takehiko Koga, Kotaro Takeshita, Yuta Maruki, Akihiro Ohba, Yoshikuni Nagashio, Shunsuke Kondo, Chigusa Morizane, Hideki Ueno, Yutaka Saito, Yasushi Yatabe, Takuji Okusaka.
       BACKGROUND: There are limited studies on the results of comprehensive genomic profiling testing for pancreatic cancer tissue specimens by endoscopic ultrasound-guided tissue acquisition (EUS-TA). This study aimed to evaluate the proportion of specimens obtained by EUS-TA using a 19-gauge (G) fine-needle biopsy (FNB) needle for unresectable pancreatic cancer (UR-PC) that met the OncoGuide™ NCC Oncopanel System (NOP) analysis suitability criteria.
    METHODS: In this single-arm, prospective, phase II study, EUS-TA was performed using a 19G FNB biopsy needle in patients with suspected UR-PC based on a contrast-enhanced computed tomography scan. The primary endpoint was the proportion of patients who met the NOP analysis suitability criteria, with a threshold, expected value, α-error, and power of 40%, 70%, 0.025, and 0.9, respectively, and the planned number of enrolled patients was 33. The NOP analysis suitability criteria were defined as tumor cell content ≥ 20% and tissue size ≥ 4 mm2.
    RESULTS: Thirty-three patients were enrolled. The procedural success rate was 100%, and the cytodiagnosis of class V was observed in all patients. The proportion of patients meeting the NOP analysis suitability criteria was 63.6% (95% CI 47.22-80.05), which satisfied the predefined criteria to be considered valid. Adverse events occurred in 9.0% of the patients.
    CONCLUSIONS: The proportion of patients with UR-PC who met the NOP analysis suitability criteria for EUS-TA using a 19G FNB needle was effective for achieving the primary endpoint, making it a valid test method. Adverse events occurred at a higher rate than that previously reported.
    Keywords:  Comprehensive genomic profiling; Endoscopic ultrasound-guided fine-needle biopsy; Endoscopic ultrasound-guided tissue acquisition; Next-generation sequencing; Pancreatic cancer
    DOI:  https://doi.org/10.1007/s00535-022-01926-z
  5. Trends Cancer. 2022 Sep 29. pii: S2405-8033(22)00190-X. [Epub ahead of print]
    Cancer fitness genes: emerging therapeutic targets for metastasis.
    Minhong Shen, Yibin Kang.
      Development of cancer therapeutics has traditionally focused on targeting driver oncogenes. Such an approach is limited by toxicity to normal tissues and treatment resistance. A class of 'cancer fitness genes' with crucial roles in metastasis have been identified. Elevated or altered activities of these genes do not directly cause cancer; instead, they relieve the stresses that tumor cells encounter and help them adapt to a changing microenvironment, thus facilitating tumor progression and metastasis. Importantly, as normal cells do not experience high levels of stress under physiological conditions, targeting cancer fitness genes is less likely to cause toxicity to noncancerous tissues. Here, we summarize the key features and function of cancer fitness genes and discuss their therapeutic potential.
    Keywords:  cancer fitness genes; cancer therapy; metastasis; stress
    DOI:  https://doi.org/10.1016/j.trecan.2022.08.007
  6. Proc Natl Acad Sci U S A. 2022 Oct 11. 119(41): e2207303119
    Mesoscale structure-function relationships in mitochondrial transcriptional condensates.
    Marina Feric, Azadeh Sarfallah, Furqan Dar, Dmitry Temiakov, Rohit V Pappu, Tom Misteli.
      In live cells, phase separation is thought to organize macromolecules into membraneless structures known as biomolecular condensates. Here, we reconstituted transcription in condensates from purified mitochondrial components using optimized in vitro reaction conditions to probe the structure-function relationships of biomolecular condensates. We find that the core components of the mt-transcription machinery form multiphasic, viscoelastic condensates in vitro. Strikingly, the rates of condensate-mediated transcription are substantially lower than in solution. The condensate-mediated decrease in transcriptional rates is associated with the formation of vesicle-like structures that are driven by the production and accumulation of RNA during transcription. The generation of RNA alters the global phase behavior and organization of transcription components within condensates. Coarse-grained simulations of mesoscale structures at equilibrium show that the components stably assemble into multiphasic condensates and that the vesicles formed in vitro are the result of dynamical arrest. Overall, our findings illustrate the complex phase behavior of transcribing, multicomponent condensates, and they highlight the intimate, bidirectional interplay of structure and function in transcriptional condensates.
    Keywords:  biomolecular condensates; mitochondrial genome; phase separation; transcription; vesicles
    DOI:  https://doi.org/10.1073/pnas.2207303119
  7. Sci Signal. 2022 Oct 04. 15(754): eadf1286
    Charting metastasis.
    Amy E Baek.
      A subpopulation of melanoma cells responds to microenvironmental cues and disseminates from lesions.
    DOI:  https://doi.org/10.1126/scisignal.adf1286
  8. Annu Rev Pathol. 2022 Oct 07.
    Orchestration of Collective Migration and Metastasis by Tumor Cell Clusters.
    Ami Yamamoto, Andrea E Doak, Kevin J Cheung.
      Metastatic dissemination has lethal consequences for cancer patients. Accruing evidence supports the hypothesis that tumor cells can migrate and metastasize as clusters of cells while maintaining contacts with one another. Collective metastasis enables tumor cells to colonize secondary sites more efficiently, resist cell death, and evade the immune system. On the other hand, tumor cell clusters face unique challenges for dissemination particularly during systemic dissemination. Here, we review recent progress toward understanding how tumor cell clusters overcome these disadvantages as well as mechanisms they utilize to gain advantages throughout the metastatic process. We consider useful models for studying collective metastasis and reflect on how the study of collective metastasis suggests new opportunities for eradicating and preventing metastatic disease. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-031521-023557
  9. Mol Cell. 2022 Oct 06. pii: S1097-2765(22)00893-0. [Epub ahead of print]82(19): 3750
    Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability.
    Gokhan Unlu, Benjamin Prizer, Ranya Erdal, Hsi-Wen Yeh, Erol C Bayraktar, Kıvanç Birsoy.
      
    DOI:  https://doi.org/10.1016/j.molcel.2022.09.004
  10. MethodsX. 2022 ;9 101856
    Whole-slide imaging and a Fiji-based image analysis workflow of immunohistochemistry staining of pancreatic islets.
    Emma Jane Buckels, Jacqueline Mary Ross, Hui Hui Phua, Frank Harry Bloomfield, Anne Louise Jaquiery.
      Quantification of cell populations in tissue sections is frequently examined in studies of human disease. However, traditional manual imaging of sections stained with immunohistochemistry is laborious, time-consuming, and often assesses fields of view rather than the whole tissue section. The analysis is usually manual or utilises expensive proprietary image analysis platforms. Whole-slide imaging allows rapid automated visualisation of entire tissue sections. This approach increases the quantum of data generated per slide, decreases user time compared to manual microscopy, and reduces selection bias. However, such large data sets mean that manual image analysis is no longer practicable, requiring an automated process. In the case of diabetes, the contribution of various pancreatic endocrine cell populations is often investigated in preclinical and clinical samples. We developed a two-part method to measure pancreatic endocrine cell mass, firstly describing imaging using an automated slide-scanner, and secondly, the analysis of the resulting large image data sets using the open-source software, Fiji, which is freely available to all researchers and has cross-platform compatibility. This protocol is highly versatile and may be applied either in full or in part to analysis of IHC images created using other imaging platforms and/or the analysis of other tissues and cell markers.
    Keywords:  Semi-automated image analysis; Sheep pancreas; Type 2 diabetes mellitus; α-cell mass; β-cell mass
    DOI:  https://doi.org/10.1016/j.mex.2022.101856
  11. Cell Metab. 2022 Oct 04. pii: S1550-4131(22)00399-0. [Epub ahead of print]34(10): 1428-1430
    Starving cancer into submission by activating BAT.
    Mohammed K Hankir, Annett Hoffmann, Florian Seyfried.
      Activated brown adipose tissue (BAT) consumes copious amounts of circulating nutrients to fuel thermogenesis. Recently writing in Nature, Seki et al. show that this property can be leveraged to limit glucose availability for cancer cells and slow tumor growth, thereby adding cancer to the growing list of diseases that can potentially be treated by activating BAT.
    DOI:  https://doi.org/10.1016/j.cmet.2022.09.009
  12. Cell Metab. 2022 Oct 04. pii: S1550-4131(22)00401-6. [Epub ahead of print]34(10): 1416-1419
    Focus on diet and exercise.
    John Speakman, Alexandra Johnstone, Trine Moholdt, Satchidananda Panda, Samuel Klein, Benjamin L Parker, Laurie Goodyear.
      Research-based lifestyle choices can help us live healthier lives, and in this issue of Cell Metabolism, we showcase articles focused on diet and exercise interventions. Here, we take a moment to learn about the motivation and challenges behind these studies and look forward to the next steps in applying these interventions to promote metabolic health.
    DOI:  https://doi.org/10.1016/j.cmet.2022.09.011
  13. Nat Commun. 2022 Oct 03. 13(1): 5745
    Multiscale profiling of protease activity in cancer.
    Ava P Amini, Jesse D Kirkpatrick, Cathy S Wang, Alex M Jaeger, Susan Su, Santiago Naranjo, Qian Zhong, Christina M Cabana, Tyler Jacks, Sangeeta N Bhatia.
      Diverse processes in cancer are mediated by enzymes, which most proximally exert their function through their activity. High-fidelity methods to profile enzyme activity are therefore critical to understanding and targeting the pathological roles of enzymes in cancer. Here, we present an integrated set of methods for measuring specific protease activities across scales, and deploy these methods to study treatment response in an autochthonous model of Alk-mutant lung cancer. We leverage multiplexed nanosensors and machine learning to analyze in vivo protease activity dynamics in lung cancer, identifying significant dysregulation that includes enhanced cleavage of a peptide, S1, which rapidly returns to healthy levels with targeted therapy. Through direct on-tissue localization of protease activity, we pinpoint S1 cleavage to the tumor vasculature. To link protease activity to cellular function, we design a high-throughput method to isolate and characterize proteolytically active cells, uncovering a pro-angiogenic phenotype in S1-cleaving cells. These methods provide a framework for functional, multiscale characterization of protease dysregulation in cancer.
    DOI:  https://doi.org/10.1038/s41467-022-32988-5
  14. Cell Metab. 2022 Sep 28. pii: S1550-4131(22)00395-3. [Epub ahead of print]
    Two independent respiratory chains adapt OXPHOS performance to glycolytic switch.
    Erika Fernández-Vizarra, Sandra López-Calcerrada, Ana Sierra-Magro, Rafael Pérez-Pérez, Luke E Formosa, Daniella H Hock, María Illescas, Ana Peñas, Michele Brischigliaro, Shujing Ding, Ian M Fearnley, Charalampos Tzoulis, Robert D S Pitceathly, Joaquín Arenas, Miguel A Martín, David A Stroud, Massimo Zeviani, Michael T Ryan, Cristina Ugalde.
      The structural and functional organization of the mitochondrial respiratory chain (MRC) remains intensely debated. Here, we show the co-existence of two separate MRC organizations in human cells and postmitotic tissues, C-MRC and S-MRC, defined by the preferential expression of three COX7A subunit isoforms, COX7A1/2 and SCAFI (COX7A2L). COX7A isoforms promote the functional reorganization of distinct co-existing MRC structures to prevent metabolic exhaustion and MRC deficiency. Notably, prevalence of each MRC organization is reversibly regulated by the activation state of the pyruvate dehydrogenase complex (PDC). Under oxidative conditions, the C-MRC is bioenergetically more efficient, whereas the S-MRC preferentially maintains oxidative phosphorylation (OXPHOS) upon metabolic rewiring toward glycolysis. We show a link between the metabolic signatures converging at the PDC and the structural and functional organization of the MRC, challenging the widespread notion of the MRC as a single functional unit and concluding that its structural heterogeneity warrants optimal adaptation to metabolic function.
    Keywords:  COX7A1–2; SCAFI/COX7RP/COX7A2L; bioenergetics; glycolysis; metabolic switch; mitochondria; oxidative metabolism; pyruvate dehydrogenase; respiratory chain organizations; respiratory supercomplexes
    DOI:  https://doi.org/10.1016/j.cmet.2022.09.005
  15. Cancer Immunol Res. 2022 Oct 07. pii: CIR-22-0225. [Epub ahead of print]
    Subcapsular sinus macrophages promote melanoma metastasis to the sentinel lymph nodes via an IL-1α-STAT3 axis.
    Tommaso Virgilio, Joy Bordini, Luciano Cascione, Giulio Sartori, Irene Latino, Daniel Molina Romero, Cristina Leoni, Murodzhon Akhmedov, Andrea Rinaldi, Alberto J Arribas, Diego Morone, S Morteza Seyed Jafari, Marina Bersudsky, Aner Ottolenghi, Ivo Kwee, Anna Maria Chiaravalli, Fausto Sessa, Robert E Hunger, Antonino Bruno, Lorenzo Mortara, Elena Voronov, Silvia Monticelli, Ron N Apte, Francesco Bertoni, Santiago F Gonzalez.
      During melanoma metastasis, tumor cells originating in the skin migrate via lymphatic vessels to the sentinel lymph nodes (sLNs). This process facilitates tumor cell spread across the body. Here, we characterized the innate inflammatory response to melanoma in the metastatic microenvironment of the sLNs. We found that macrophages located in the subcapsular sinus (SS) produced pro-tumoral IL-1α after recognition of tumoral antigens. Moreover, we confirmed that the elimination of LN macrophages or the administration of an IL-1α-specific blocking antibody reduced metastatic spread. To understand the mechanism of action of IL-1α in the context of the sLN microenvironment, we applied single-cell RNA sequencing to microdissected metastases obtained from animals treated with the IL-1α-specific blocking antibody. Amongst the different pathways affected, we identified STAT3 as one of the main targets of IL-1α signaling in metastatic tumor cells. Moreover, we found that the antitumoral effect of the anti-IL-1α was not mediated by lymphocytes because Il1r1 knockout mice did not show significant differences in metastasis growth. Finally, we found a synergistic anti-metastatic effect of the combination of IL-1α blockade and STAT3 inhibition with stattic, highlighting a new immunotherapy approach to preventing melanoma metastasis.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0225
  16. Int J Biochem Cell Biol. 2022 Sep 20. pii: S1357-2725(22)00145-5. [Epub ahead of print]152 106300
    The multifaceted role of micronuclei in tumour progression: A whole organism perspective.
    Molly Guscott, Akash Saha, Jovanna Maharaj, Sarah E McClelland.
      Within most tumour types, cancerous cells exist in a state of aneuploidy, an incorrect chromosome number or structure. Additionally, tumour cells frequently exhibit chromosomal instability; the ongoing loss or gain of whole or parts of chromosomes during cell division. Chromosomal instability results in a high rate of chromosome segregation defects, and a constantly changing genomic landscape. A second consequence of recurrent chromosome segregation defects is the exclusion of mis-segregated chromatin from the newly reforming nucleus. Chromosomes, or chromosome fragments that are not incorporated into the main nucleus are often packaged into extranuclear structures called micronuclei. While the initial impact of micronucleus formation is an imbalance or loss of genetic material in the resulting daughter cells, several other downstream consequences are now known to result from this process. In this review, we discuss the further consequences of micronucleus formation, including how structural changes to the micronuclear envelope, and the rupturing of micronuclear membranes can contribute to metastasis, immune cell activation and overall, tumour progression.
    Keywords:  CGAS; Cancer; Chromosomal instability; Micronuclei; Nuclear envelope; STING
    DOI:  https://doi.org/10.1016/j.biocel.2022.106300
  17. Soft Matter. 2022 Oct 07.
    Interplay between substrate rigidity and tissue fluidity regulates cell monolayer spreading.
    Michael F Staddon, Michael P Murrell, Shiladitya Banerjee.
      Coordinated and cooperative motion of cells is essential for embryonic development, tissue morphogenesis, wound healing and cancer invasion. A predictive understanding of the emergent mechanical behaviors in collective cell motion is challenging due to the complex interplay between cell-cell interactions, cell-matrix adhesions and active cell behaviors. To overcome this challenge, we develop a predictive cellular vertex model that can delineate the relative roles of substrate rigidity, tissue mechanics and active cell properties on the movement of cell collectives. We apply the model to the specific case of collective motion in cell aggregates as they spread into a two-dimensional cell monolayer adherent to a soft elastic matrix. Consistent with recent experiments, we find that substrate stiffness regulates the driving forces for the spreading of cellular monolayer, which can be pressure-driven or crawling-based depending on substrate rigidity. On soft substrates, cell monolayer spreading is driven by an active pressure due to the influx of cells coming from the aggregate, whereas on stiff substrates, cell spreading is driven primarily by active crawling forces. Our model predicts that cooperation of cell crawling and tissue pressure drives faster spreading, while the spreading rate is sensitive to the mechanical properties of the tissue. We find that solid tissues spread faster on stiff substrates, with spreading rate increasing with tissue tension. By contrast, the spreading of fluid tissues is independent of substrate stiffness and is slower than solid tissues. We compare our theoretical results with experimental results on traction force generation and spreading kinetics of cell monolayers, and provide new predictions on the role of tissue fluidity and substrate rigidity on collective cell motion.
    DOI:  https://doi.org/10.1039/d2sm00757f
  18. Nat Methods. 2022 Oct 05.
    Sequencing single cells without killing.
    Lin Tang.
      
    DOI:  https://doi.org/10.1038/s41592-022-01648-3
  19. Aging Cancer. 2022 Jun;3(2): 87-94
    Cancer and aging: A call to action.
    Dejana Braithwaite, Stephen Anton, Supriya Mohile, James DeGregori, Nancy Gillis, Daohong Zhou, Shirley Bloodworth, Marco Pahor, Jonathan Licht.
       Background: The intersection of cancer and aging is an emerging public health challenge in developed countries because of the aging and expansion of the population.
    Aims: We convened a panel of experts to share their insights on this topic at the inaugural University of Florida Health Cancer Center's (UFHCC's) Cancer and Aging Symposium, which was held virtually in February 2022.
    Methods: We featured presentations from four leading scientists, whose research spans multiple disciplines including basic science, translational research, geriatric oncology, and population science.
    Results: Each speaker offered their unique perspective and insight on the intersection between cancer and aging and discussed their current and ongoing research in this field. In addition to this panel of experts, scientists from the National Institutes of Health and the National Cancer Institute, as well as a UFHCC-affiliated citizen scientist, shared their perspectives on strategies to move the field forward. Some of the key open questions and opportunities for future research offered by these presenters in aging and cancer include but are not limited to infusing health disparities research into the field of cancer and aging, assessing the value of geriatric assessment in identifying early vulnerabilities that may affect response to emerging cancer therapies in older patients, and assessing biological age and other biomarkers (e.g., clonal hematopoiesis) in relation to clinical endpoints and the development of primary, secondary, and tertiary cancer prevention interventions.
    Conclusion: Research is needed to accelerate knowledge regarding the dynamic interplay of cancer and aging and optimize care in diverse older adults to achieve equity in cancer outcomes.
    Keywords:  aging; cancer; transdisciplinary science
    DOI:  https://doi.org/10.1002/aac2.12055
  20. Signal Transduct Target Ther. 2022 Oct 02. 7(1): 341
    Cancer metastasis chemoprevention prevents circulating tumour cells from germination.
    Xiaodong Xie, Yumei Li, Shu Lian, Yusheng Lu, Lee Jia.
      The war against cancer traces back to the signature event half-a-century ago when the US National Cancer Act was signed into law. The cancer crusade costs trillions with disappointing returns, teasing the possibility of a new breakthrough. Cure for cancer post-metastases still seems tantalisingly out of reach. Once metastasized, cancer-related death is extremely difficult, if not impossible, to be reversed. Here we present cancer pre-metastasis chemoprevention strategy that can prevent circulating tumour cells (CTCs) from initiating metastases safely and effectively, and is disparate from the traditional cancer chemotherapy and cancer chemoprevention. Deep learning of the biology of CTCs and their disseminating organotropism, complexity of their adhesion to endothelial niche reveals that if the adhesion of CTCs to their metastasis niche (the first and the most important part in cancer metastatic cascade) can be pharmaceutically interrupted, the lethal metastatic cascade could be prevented from getting initiated. We analyse the key inflammatory and adhesive factors contributing to CTC adhesion/germination, provide pharmacological fundamentals for abortifacients to intervene CTC adhesion to the distant metastasis sites. The adhesion/inhibition ratio (AIR) is defined for selecting the best cancer metastasis chemopreventive candidates. The successful development of such new therapeutic modalities for cancer metastasis chemoprevention has great potential to revolutionise the current ineffective post-metastasis treatments.
    DOI:  https://doi.org/10.1038/s41392-022-01174-w
  21. Bioinformatics. 2022 Oct 07. pii: btac665. [Epub ahead of print]
    RPPA SPACE: An R package for normalization and quantitation of Reverse-Phase Protein Array (RPPA) data.
    Huma Shehwana, Shwetha V Kumar, James M Melott, Mary A Rohrdanz, Chris Wakefield, Zhenlin Ju, Doris R Siwak, Yiling Lu, Bradley M Broom, John N Weinstein, Gordon B Mills, Rehan Akbani.
       SUMMARY: Reverse Phase Protein Array (RPPA) is a robust high-throughput, cost effective platform for quantitatively measuring proteins in biological specimens. However, converting raw RPPA data into normalized, analysis-ready data remains a challenging task. Here, we present the RPPA SPACE R package, a substantially improved successor to SuperCurve, to meet that challenge. SuperCurve has been used to normalize over 170,000 samples to date. RPPA SPACE allows exclusion of poor-quality samples from the normalization process to improve the quality of the remaining samples. It also features a novel quality-control metric, "noise," that estimates the level of random errors present in each RPPA slide. The noise metric can help to determine the quality and reliability of the data. In addition, RPPA SPACE has simpler input requirements and is more flexible than SuperCurve, it is much faster with greatly improved error reporting.
    AVAILABILITY AND IMPLEMENTATION: The standalone RPPA SPACE R package, tutorials and sample data are available via https://rppa.space/, CRAN (https://cran.r-project.org/web/packages/RPPASPACE/index.html), and GitHub (https://github.com/MD-Anderson-Bioinformatics/RPPASPACE).
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btac665
  22. Sci Data. 2022 Oct 07. 9(1): 607
    TumorMet: A repository of tumor metabolic networks derived from context-specific Genome-Scale Metabolic Models.
    Ilaria Granata, Ichcha Manipur, Maurizio Giordano, Lucia Maddalena, Mario Rosario Guarracino.
      Studies about the metabolic alterations during tumorigenesis have increased our knowledge of the underlying mechanisms and consequences, which are important for diagnostic and therapeutic investigations. In this scenario and in the era of systems biology, metabolic networks have become a powerful tool to unravel the complexity of the cancer metabolic machinery and the heterogeneity of this disease. Here, we present TumorMet, a repository of tumor metabolic networks extracted from context-specific Genome-Scale Metabolic Models, as a benchmark for graph machine learning algorithms and network analyses. This repository has an extended scope for use in graph classification, clustering, community detection, and graph embedding studies. Along with the data, we developed and provided Met2Graph, an R package for creating three different types of metabolic graphs, depending on the desired nodes and edges: Metabolites-, Enzymes-, and Reactions-based graphs. This package allows the easy generation of datasets for downstream analysis.
    DOI:  https://doi.org/10.1038/s41597-022-01702-x
  23. Nat Commun. 2022 Oct 02. 13(1): 5797
    Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer.
    Lea Monteran, Nour Ershaid, Hila Doron, Yael Zait, Ye'ela Scharff, Shahar Ben-Yosef, Camila Avivi, Iris Barshack, Amir Sonnenblick, Neta Erez.
      Mortality from breast cancer is almost exclusively a result of tumor metastasis and resistance to therapy and therefore understanding the underlying mechanisms is an urgent challenge. Chemotherapy, routinely used to treat breast cancer, induces extensive tissue damage, eliciting an inflammatory response that may hinder efficacy and promote metastatic relapse. Here we show that systemic treatment with doxorubicin, but not cisplatin, following resection of a triple-negative breast tumor induces the expression of complement factors in lung fibroblasts and modulates an immunosuppressive metastatic niche that supports lung metastasis. Complement signaling derived from cancer-associated fibroblasts (CAFs) mediates the recruitment of myeloid-derived suppressor cells (MDSCs) to the metastatic niche, thus promoting T cell dysfunction. Pharmacological targeting of complement signaling in combination with chemotherapy alleviates immune dysregulation and attenuates lung metastasis. Our findings suggest that combining cytotoxic treatment with blockade of complement signaling in triple-negative breast cancer patients may attenuate the adverse effects of chemotherapy, thus offering a promising approach for clinical use.
    DOI:  https://doi.org/10.1038/s41467-022-33598-x
  24. Pancreas. 2022 Jul 01. 51(6): 678-683
    Telomere Attrition in Intraductal Papillary Mucinous Neoplasms of the Pancreas Associated With Carcinogenesis and Aging.
    Atsushi Miki, Yoko Matsuda, Junko Aida, Jun Watanabe, Yukihiro Sanada, Yasunaru Sakuma, Alan K Lefor, Noriyoshi Fukushima, Naohiro Sata, Tomio Arai, Kaiyo Takubo, Toshiyuki Ishiwata.
       OBJECTIVES: It is challenging to preoperatively distinguish malignant and benign forms of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. The aims of this study were to investigate whether telomere length is associated with pathological grade of IPMNs and age and to clarify the utility of telomere length as a marker to identify malignant IPMNs.
    METHODS: Pancreas tissue was obtained from 28 patients after resection. We measured the telomere lengths of tumor cells in IPMNs and normal duct cells by quantitative fluorescence in situ hybridization. The association of normalized telomere-centromere ratio (NTCR) to pathological grade of IPMNs and age were determined.
    RESULTS: The NTCR showed a gradual decrease with increasing pathological grade of IPMNs. The NTCR in intermediate- and high-grade dysplasia and adenocarcinoma lesions was significantly shorter than in normal pancreatic ducts (P < 0.05). In multivariate analysis, telomere length was most associated with carcinogenesis. When the cutoff value of NTCR was set to 0.74, the sensitivity for detection of high-grade dysplasia and adenocarcinoma was 82.8%, with a specificity of 87.5%.
    CONCLUSIONS: Telomere shortening occurs with carcinogenesis and aging. A significant reduction of telomere length in IPMNs may be useful for surgical decision making.
    DOI:  https://doi.org/10.1097/MPA.0000000000002081
  25. J Am Chem Soc. 2022 Oct 03.
    Lipid Expansion Microscopy.
    Brittany M White, Pratik Kumar, Amanda N Conwell, Kane Wu, Jeremy M Baskin.
      Strategies to visualize cellular membranes with light microscopy are restricted by the diffraction limit of light, which far exceeds the dimensions of lipid bilayers. Here, we describe a method for super-resolution imaging of metabolically labeled phospholipids within cellular membranes. Guided by the principles of expansion microscopy, we develop an all-small molecule approach that enables direct chemical anchoring of bioorthogonally labeled phospholipids into a hydrogel network and is capable of super-resolution imaging of cellular membranes. We apply this method, termed lipid expansion microscopy (LExM), to visualize organelle membranes with precision, including a unique class of membrane-bound structures known as nuclear invaginations. Compatible with standard confocal microscopes, LExM will be widely applicable for super-resolution imaging of phospholipids and cellular membranes in numerous physiological contexts.
    DOI:  https://doi.org/10.1021/jacs.2c03743
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