bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023–01–15
35 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Context-Specific Determinants of the Immunosuppressive Tumor Microenvironment in Pancreatic Cancer.
  2. Intravital imaging of Wnt/β-catenin and ATF2-dependent signalling pathways during tumour cell invasion and metastasis.
  3. Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan.
  4. Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth.
  5. Targeted and explorative profiling of kallikrein proteases and global proteome biology of pancreatic ductal adenocarcinoma, chronic pancreatitis, and normal pancreas highlights disease-specific proteome remodelling.
  6. Cancer-Associated Fibroblast Diversity Shapes Tumor Metabolism in Pancreatic Cancer.
  7. An atlas of substrate specificities for the human serine/threonine kinome.
  8. An intrasplenic injection model of pancreatic cancer metastasis to the liver in mice.
  9. Control of tumor-associated macrophage responses by nutrient acquisition and metabolism.
  10. GDF15 neutralization restores muscle function and physical performance in a mouse model of cancer cachexia.
  11. LYSET/TMEM251/GCAF is critical for autophagy and lysosomal function by regulating the mannose-6-phosphate (M6P) pathway.
  12. LAP1 supports nuclear adaptability during constrained melanoma cell migration and invasion.
  13. A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma.
  14. Progressive development of melanoma-induced cachexia differentially impacts organ systems in mice.
  15. Where is the field of autophagy research heading?
  16. RNA splicing dysregulation and the hallmarks of cancer.
  17. Optimized protocol for the generation of an orthotopic colon cancer mouse model and metastasis.
  18. p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression.
  19. The CAM Model-Q&A with Experts.
  20. Targeting TBK1 to overcome resistance to cancer immunotherapy.
  21. Multistain deep learning for prediction of prognosis and therapy response in colorectal cancer.
  22. Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy.
  23. Loss of epigenetic information as a cause of mammalian aging.
  24. Overexpression of Pdx1, reduction of p53, or deletion of CHOP attenuates pancreas hypoplasia in mice with pancreas-specific O-GlcNAc Transferase deletion.
  25. Sensitive imaging of Endoplasmic reticulum (ER) autophagy with an acidity-reporting ER-Tracker.
  26. Muc4 loss mitigates epidermal growth factor receptor activity essential for PDAC tumorigenesis.
  27. Humanized mouse models for immuno-oncology research.
  28. Addressing the genetic/nongenetic duality in cancer with systems biology.
  29. Biological age and environmental risk factors for dementia and stroke: Molecular mechanisms.
  30. A biomimetic nanodrug for enhanced chemotherapy of pancreatic tumors.
  31. Cell size and actin architecture determine force generation in optogenetically activated cells.
  32. Seeing is great, understanding is better.
  33. Mechanosensitive Channel-Based Optical Membrane Tension Reporter.
  34. Understanding and modeling nerve-cancer interactions.
  35. Prognostic implications of microRNA-21 overexpression in pancreatic ductal adenocarcinoma: an international multicenter study of 686 patients.
  1. Cancer Discov. 2023 Jan 09. OF1-OF20
    Context-Specific Determinants of the Immunosuppressive Tumor Microenvironment in Pancreatic Cancer.
    Chiara Falcomatà, Stefanie Bärthel, Günter Schneider, Roland Rad, Marc Schmidt-Supprian, Dieter Saur.
       ABSTRACT: Immunotherapies have shown benefits across a range of human cancers, but not pancreatic ductal adenocarcinoma (PDAC). Recent evidence suggests that the immunosuppressive tumor microenvironment (TME) constitutes an important roadblock to their efficacy. The landscape of the TME differs substantially across PDAC subtypes, indicating context-specific principles of immunosuppression. In this review, we discuss how PDAC cells, the local TME, and systemic host and environmental factors drive immunosuppression in context. We argue that unraveling the mechanistic drivers of the context-specific modes of immunosuppression will open new possibilities to target PDAC more efficiently by using multimodal (immuno)therapeutic interventions.
    SIGNIFICANCE: Immunosuppression is an almost universal hallmark of pancreatic cancer, although this tumor entity is highly heterogeneous across its different subtypes and phenotypes. Here, we provide evidence that the diverse TME of pancreatic cancer is a central executor of various different context-dependent modes of immunosuppression, and discuss key challenges and novel opportunities to uncover, functionalize, and target the central drivers and functional nodes of immunosuppression for therapeutic exploitation.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0876
  2. J Cell Sci. 2023 Jan 09. pii: jcs.260285. [Epub ahead of print]
    Intravital imaging of Wnt/β-catenin and ATF2-dependent signalling pathways during tumour cell invasion and metastasis.
    Konstantin Stoletov, Saray Sanchez, Irantzu Gorroño, Miriam Rabano, Maria Vivanco, Robert Kypta, John D Lewis.
      Wnt signalling is implicated as a driver of tumour cell metastasis, but less is known about which branches of Wnt signalling are involved and when they act in the metastatic cascade. Using a unique intravital imaging platform and fluorescent reporters, we visualised Wnt/β-catenin/TCF/LEF-dependent and ATF2-dependent signalling activities during human cancer cell invasion, intravasation and metastatic lesion formation in the chick embryo host. We found that cancer cells readily shifted between states of low and high canonical Wnt activity. Cancer cells that displayed low Wnt canonical activity showed higher invasion and intravasation potential in primary tumours and in metastatic lesions. In contrast, cancer cells showing low ATF2-dependent activity were significantly less invasive both at the front of primary tumours and in metastatic lesions. Simultaneous visualisation of both these reporters using a double reporter cell line confirmed their complementary activities in primary tumours and metastatic lesions. These findings may inform the development of therapies that target different branches of Wnt signalling at specific stages of metastasis.
    Keywords:   in vivo imaging; Cancer metastasis; Wnt
    DOI:  https://doi.org/10.1242/jcs.260285
  3. Cell. 2023 Jan 05. pii: S0092-8674(22)01520-3. [Epub ahead of print]186(1): 63-79.e21
    Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan.
    Clara Correia-Melo, Stephan Kamrad, Roland Tengölics, Christoph B Messner, Pauline Trebulle, StJohn Townsend, Sreejith Jayasree Varma, Anja Freiwald, Benjamin M Heineike, Kate Campbell, Lucía Herrera-Dominguez, Simran Kaur Aulakh, Lukasz Szyrwiel, Jason S L Yu, Aleksej Zelezniak, Vadim Demichev, Michael Mülleder, Balázs Papp, Mohammad Tauqeer Alam, Markus Ralser.
      Metabolism is deeply intertwined with aging. Effects of metabolic interventions on aging have been explained with intracellular metabolism, growth control, and signaling. Studying chronological aging in yeast, we reveal a so far overlooked metabolic property that influences aging via the exchange of metabolites. We observed that metabolites exported by young cells are re-imported by chronologically aging cells, resulting in cross-generational metabolic interactions. Then, we used self-establishing metabolically cooperating communities (SeMeCo) as a tool to increase metabolite exchange and observed significant lifespan extensions. The longevity of the SeMeCo was attributable to metabolic reconfigurations in methionine consumer cells. These obtained a more glycolytic metabolism and increased the export of protective metabolites that in turn extended the lifespan of cells that supplied them with methionine. Our results establish metabolite exchange interactions as a determinant of cellular aging and show that metabolically cooperating cells can shape the metabolic environment to extend their lifespan.
    Keywords:  chronological aging; eukaryotic longevity; metabolic microenvironment; metabolite exchange interactions
    DOI:  https://doi.org/10.1016/j.cell.2022.12.007
  4. Nat Cell Biol. 2023 Jan 12.
    Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth.
    Rui Tang, Emily G Shuldiner, Marcus Kelly, Christopher W Murray, Jess D Hebert, Laura Andrejka, Min K Tsai, Nicholas W Hughes, Mitchell I Parker, Hongchen Cai, Yao-Cheng Li, Geoffrey M Wahl, Roland L Dunbrack, Peter K Jackson, Dmitri A Petrov, Monte M Winslow.
      Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to treat, and our understanding of the regulators of RAS signalling is incomplete. Here to uncover the impact of diverse KRAS-interacting proteins on lung cancer growth, we combined multiplexed somatic CRISPR/Cas9-based genome editing in genetically engineered mouse models with tumour barcoding and high-throughput barcode sequencing. Through a series of CRISPR/Cas9 screens in autochthonous lung cancer models, we show that HRAS and NRAS are suppressors of KRASG12D-driven tumour growth in vivo and confirm these effects in oncogenic KRAS-driven human lung cancer cell lines. Mechanistically, RAS paralogues interact with oncogenic KRAS, suppress KRAS-KRAS interactions, and reduce downstream ERK signalling. Furthermore, HRAS and NRAS mutations identified in oncogenic KRAS-driven human tumours partially abolished this effect. By comparing the tumour-suppressive effects of HRAS and NRAS in oncogenic KRAS- and oncogenic BRAF-driven lung cancer models, we confirm that RAS paralogues are specific suppressors of KRAS-driven lung cancer in vivo. Our study outlines a technological avenue to uncover positive and negative regulators of oncogenic KRAS-driven cancer in a multiplexed manner in vivo and highlights the role RAS paralogue imbalance in oncogenic KRAS-driven lung cancer.
    DOI:  https://doi.org/10.1038/s41556-022-01049-w
  5. Neoplasia. 2023 Jan 05. pii: S1476-5586(22)00096-3. [Epub ahead of print]36 100871
    Targeted and explorative profiling of kallikrein proteases and global proteome biology of pancreatic ductal adenocarcinoma, chronic pancreatitis, and normal pancreas highlights disease-specific proteome remodelling.
    Janina Werner, Patrick Bernhard, Miguel Cosenza-Contreras, Niko Pinter, Matthias Fahrner, Prama Pallavi, Johannes Eberhard, Peter Bronsert, Felix Rückert, Oliver Schilling.
      Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive and lethal malignancies worldwide with an urgent need for new diagnostic and therapeutic strategies. One major risk factor for PDAC is the pre-indication of chronic pancreatitis (CP), which represents highly inflammatory pancreatic tissue. Kallikreins (KLKs) are secreted serine proteases that play an important role in various cancers as components of the tumor microenvironment. Previous studies of KLKs in solid tumors largely relied on either transcriptomics or immunodetection. We present one of the first targeted mass spectrometry profiling of kallikrein proteases in PDAC, CP, and normal pancreas. We show that KLK6 and KLK10 are significantly upregulated in PDAC (n=14) but not in CP (n=7) when compared to normal pancreas (n=16), highlighting their specific intertwining with malignancy. Additional explorative proteome profiling identified 5936 proteins in our pancreatic cohort and observed disease-specific proteome rearrangements in PDAC and CP. As such, PDAC features an enriched proteome motif for extracellular matrix (ECM) and cell adhesion while there is depletion of mitochondrial energy metabolism proteins, reminiscent of the Warburg effect. Although often regarded as a PDAC hallmark, the ECM fingerprint was also observed in CP, alongside with a prototypical inflammatory proteome motif as well as with an increased wound healing process and proteolytic activity, thereby possibly illustrating tissue autolysis. Proteogenomic analysis based on publicly accessible data sources identified 112 PDAC-specific and 32 CP-specific single amino acid variants, which among others affect KRAS and ANKHD1. Our study emphasizes the diagnostic potential of kallikreins and provides novel insights into proteomic characteristics of PDAC and CP.
    Keywords:  FFPE; KLK; Mass Spectrometry; PDAC
    DOI:  https://doi.org/10.1016/j.neo.2022.100871
  6. Cancers (Basel). 2022 Dec 22. pii: 61. [Epub ahead of print]15(1):
    Cancer-Associated Fibroblast Diversity Shapes Tumor Metabolism in Pancreatic Cancer.
    Raphaël Peiffer, Yasmine Boumahd, Charlotte Gullo, Rebekah Crake, Elisabeth Letellier, Akeila Bellahcène, Olivier Peulen.
      Despite extensive research, the 5-year survival rate of pancreatic cancer (PDAC) patients remains at only 9%. Patients often show poor treatment response, due partly to a highly complex tumor microenvironment (TME). Cancer-associated fibroblast (CAF) heterogeneity is characteristic of the pancreatic TME, where several CAF subpopulations have been identified, such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen presenting CAFs (apCAFs). In PDAC, cancer cells continuously adapt their metabolism (metabolic switch) to environmental changes in pH, oxygenation, and nutrient availability. Recent advances show that these environmental alterations are all heavily driven by stromal CAFs. CAFs and cancer cells exchange cytokines and metabolites, engaging in a tight bidirectional crosstalk, which promotes tumor aggressiveness and allows constant adaptation to external stress, such as chemotherapy. In this review, we summarize CAF diversity and CAF-mediated metabolic rewiring, in a PDAC-specific context. First, we recapitulate the most recently identified CAF subtypes, focusing on the cell of origin, activation mechanism, species-dependent markers, and functions. Next, we describe in detail the metabolic crosstalk between CAFs and tumor cells. Additionally, we elucidate how CAF-driven paracrine signaling, desmoplasia, and acidosis orchestrate cancer cell metabolism. Finally, we highlight how the CAF/cancer cell crosstalk could pave the way for new therapeutic strategies.
    Keywords:  CAF; PDAC; acidosis; cancer-associated fibroblast; desmoplasia; hypoxia; metabolism; pancreatic cancer; paracrine signaling
    DOI:  https://doi.org/10.3390/cancers15010061
  7. Nature. 2023 Jan 11.
    An atlas of substrate specificities for the human serine/threonine kinome.
    Jared L Johnson, Tomer M Yaron, Emily M Huntsman, Alexander Kerelsky, Junho Song, Amit Regev, Ting-Yu Lin, Katarina Liberatore, Daniel M Cizin, Benjamin M Cohen, Neil Vasan, Yilun Ma, Konstantin Krismer, Jaylissa Torres Robles, Bert van de Kooij, Anne E van Vlimmeren, Nicole Andrée-Busch, Norbert F Käufer, Maxim V Dorovkov, Alexey G Ryazanov, Yuichiro Takagi, Edward R Kastenhuber, Marcus D Goncalves, Benjamin D Hopkins, Olivier Elemento, Dylan J Taatjes, Alexandre Maucuer, Akio Yamashita, Alexei Degterev, Mohamed Uduman, Jingyi Lu, Sean D Landry, Bin Zhang, Ian Cossentino, Rune Linding, John Blenis, Peter V Hornbeck, Benjamin E Turk, Michael B Yaffe, Lewis C Cantley.
      Protein phosphorylation is one of the most widespread post-translational modifications in biology1,2. With advances in mass-spectrometry-based phosphoproteomics, 90,000 sites of serine and threonine phosphorylation have so far been identified, and several thousand have been associated with human diseases and biological processes3,4. For the vast majority of phosphorylation events, it is not yet known which of the more than 300 protein serine/threonine (Ser/Thr) kinases encoded in the human genome are responsible3. Here we used synthetic peptide libraries to profile the substrate sequence specificity of 303 Ser/Thr kinases, comprising more than 84% of those predicted to be active in humans. Viewed in its entirety, the substrate specificity of the kinome was substantially more diverse than expected and was driven extensively by negative selectivity. We used our kinome-wide dataset to computationally annotate and identify the kinases capable of phosphorylating every reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small minority of phosphosites for which the putative protein kinases involved have been previously reported, our predictions were in excellent agreement. When this approach was applied to examine the signalling response of tissues and cell lines to hormones, growth factors, targeted inhibitors and environmental or genetic perturbations, it revealed unexpected insights into pathway complexity and compensation. Overall, these studies reveal the intrinsic substrate specificity of the human Ser/Thr kinome, illuminate cellular signalling responses and provide a resource to link phosphorylation events to biological pathways.
    DOI:  https://doi.org/10.1038/s41586-022-05575-3
  8. STAR Protoc. 2023 Jan 12. pii: S2666-1667(22)00901-7. [Epub ahead of print]4(1): 102021
    An intrasplenic injection model of pancreatic cancer metastasis to the liver in mice.
    Megan O'Brien, Matthias Ernst, Ashleigh R Poh.
      Here, we provide a protocol for an intrasplenic injection model to establish pancreatic tumors in the mouse liver. We describe the steps to inject tumor cells into mouse spleen and to perform a splenectomy, followed by animal recovery and end point analysis of tumors in the liver. This model allows rapid and reproducible tumor growth in a clinically relevant metastatic site, providing a platform to evaluate the efficacy of anti-cancer drugs. This technique can be expanded to other cancer cell lines. For complete details on the use and execution of this protocol, please refer to Poh et al. (2022).1.
    Keywords:  Cancer; Cell Biology; Cell culture; Immunology; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2022.102021
  9. Immunity. 2023 Jan 10. pii: S1074-7613(22)00639-2. [Epub ahead of print]56(1): 14-31
    Control of tumor-associated macrophage responses by nutrient acquisition and metabolism.
    Xian Zhang, Liangliang Ji, Ming O Li.
      Metazoan tissue specification is associated with integration of macrophage lineage cells in sub-tissular niches to promote tissue development and homeostasis. Oncogenic transformation, most prevalently of epithelial cell lineages, results in maladaptation of resident tissue macrophage differentiation pathways to generate parenchymal and interstitial tumor-associated macrophages that largely foster cancer progression. In addition to growth factors, nutrients that can be consumed, stored, recycled, or converted to signaling molecules have emerged as crucial regulators of macrophage responses in tumor. Here, we review how nutrient acquisition through plasma membrane transporters and engulfment pathways control tumor-associated macrophage differentiation and function. We also discuss how nutrient metabolism regulates tumor-associated macrophages and how these processes may be targeted for cancer therapy.
    Keywords:  engulfment; macrophage; metabolism; nutrient; transporter; tumor
    DOI:  https://doi.org/10.1016/j.immuni.2022.12.003
  10. Cell Rep. 2023 Jan 10. pii: S2211-1247(22)01848-4. [Epub ahead of print]42(1): 111947
    GDF15 neutralization restores muscle function and physical performance in a mouse model of cancer cachexia.
    Ja Young Kim-Muller, LouJin Song, Brianna LaCarubba Paulhus, Evanthia Pashos, Xiangping Li, Anthony Rinaldi, Stephanie Joaquim, John C Stansfield, Jiangwei Zhang, Andrew Robertson, Jincheng Pang, Alan Opsahl, Magalie Boucher, Danna Breen, Katherine Hales, Abdul Sheikh, Zhidan Wu, Bei B Zhang.
      Cancer cachexia is a disorder characterized by involuntary weight loss and impaired physical performance. Decline in physical performance of patients with cachexia is associated with poor quality of life, and currently there are no effective pharmacological interventions that restore physical performance. Here we examine the effect of GDF15 neutralization in a mouse model of cancer-induced cachexia (TOV21G) that manifests weight loss and muscle function impairments. With comprehensive assessments, our results demonstrate that cachectic mice treated with the anti-GDF15 antibody mAB2 exhibit body weight gain with near-complete restoration of muscle mass and markedly improved muscle function and physical performance. Mechanistically, the improvements induced by GDF15 neutralization are primarily attributed to increased caloric intake, while altered gene expression in cachectic muscles is restored in caloric-intake-dependent and -independent manners. The findings indicate potential of GDF15 neutralization as an effective therapy to enhance physical performance of patients with cachexia.
    Keywords:  CP: Cancer; CP: Metabolism; GDF15; TOV21G; animal model of cancer cachexia; anti-GDF15 intervention; cachexia; mAB2; muscle; pair feeding; physical performance; transcriptomics profiling
    DOI:  https://doi.org/10.1016/j.celrep.2022.111947
  11. Autophagy. 2023 Jan 12.
    LYSET/TMEM251/GCAF is critical for autophagy and lysosomal function by regulating the mannose-6-phosphate (M6P) pathway.
    Bokai Zhang, Xi Yang, Ming Li.
      Vertebrate cells rely on mannose-6-phosphate (M6P) modifications to deliver most lumenal hydrolases to the lysosome. As a critical trafficking signal for lysosomal enzymes, the M6P biosynthetic pathway has been thoroughly investigated. However, its regulatory mechanism is largely unknown. Here, we summarize three recent studies that independently discovered LYSET/TMEM251/GCAF as a key regulator of the M6P pathway. LYSET/TMEM251 directly interacts with GNPT, the enzyme that catalyzes the transfer of M6P, and is critical for its activity and stability. Deleting LYSET/TMEM251 impairs the GNPT function and M6P modifications. Consequently, lysosomal enzymes are mistargeted for secretion. Defective lysosomes fail to degrade cargoes such as endocytic vesicles and autophagosomes, leading to a newly identified lysosomal storage disease in humans. These discoveries open up a new direction in the regulation of the M6P biosynthetic pathway.
    Keywords:  Autophagy; GNPT; M6P; TMEM251; lysosomal enzymes; lysosomal storage disease
    DOI:  https://doi.org/10.1080/15548627.2023.2167375
  12. Nat Cell Biol. 2023 Jan 09.
    LAP1 supports nuclear adaptability during constrained melanoma cell migration and invasion.
    Yaiza Jung-Garcia, Oscar Maiques, Joanne Monger, Irene Rodriguez-Hernandez, Bruce Fanshawe, Marie-Charlotte Domart, Matthew J Renshaw, Rosa M Marti, Xavier Matias-Guiu, Lucy M Collinson, Victoria Sanz-Moreno, Jeremy G Carlton.
      Metastasis involves dissemination of cancer cells away from a primary tumour and colonization at distal sites. During this process, the mechanical properties of the nucleus must be tuned since they pose a challenge to the negotiation of physical constraints imposed by the microenvironment and tissue structure. We discovered increased expression of the inner nuclear membrane protein LAP1 in metastatic melanoma cells, at the invasive front of human primary melanoma tumours and in metastases. Human cells express two LAP1 isoforms (LAP1B and LAP1C), which differ in their amino terminus. Here, using in vitro and in vivo models that recapitulate human melanoma progression, we found that expression of the shorter isoform, LAP1C, supports nuclear envelope blebbing, constrained migration and invasion by allowing a weaker coupling between the nuclear envelope and the nuclear lamina. We propose that LAP1 renders the nucleus highly adaptable and contributes to melanoma aggressiveness.
    DOI:  https://doi.org/10.1038/s41556-022-01042-3
  13. J Gastrointest Oncol. 2022 Dec;13(6): 3216-3226
    A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma.
    Kyaw L Aung, Elaine McWhirter, Stephen Welch, Lisa Wang, Sophia Lovell, Lee-Anne Stayner, Saara Ali, Anne Malpage, Barbara Makepeace, Makilpriya Ramachandran, Gun Ho Jang, Steven Gallinger, Tong Zhang, Tracy L Stockley, Sandra E Fischer, Neesha Dhani, David Hedley, Jennifer J Knox, Lillian L Siu, Rachel Goodwin, Philippe L Bedard.
       Background: Mitogen-activated protein kinase kinase (MEK) is activated by mutated KRAS in >90% of pancreatic ductal adenocarcinoma (PDAC). MEK and focal adhesion kinase (FAK) are frequently co-activated in PDAC providing a rationale for combining trametinib, an oral allosteric MEK1/2 inhibitor, with GSK2256098, an oral FAK inhibitor.
    Methods: Advanced PDAC patients whose disease progressed after first line palliative chemotherapy were treated with GSK2256098 250 mg twice daily and trametinib 0.5 mg once daily orally. The primary endpoint was clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks). Twenty-four patients were planned to enroll using a 2-stage minimax design (P0=0.15, P1=0.40; alpha =0.05, power 0.86). The combination would be considered inactive if 2/12 or fewer patients achieved CB at the end of stage 1, and would be considered active if >7/24 response-evaluable patients achieved CB by the end of stage 2. Serial blood samples were collected for circulating tumor DNA (ctDNA) mutation profiling.
    Results: Sixteen patients were enrolled and 11 were response evaluable. Of those 11, 10 had progressive disease as best tumor response and one had stable disease for 4 months. No treatment related grade ≥3 adverse events (AEs) were observed. The median progression free survival (PFS) was 1.6 (95% CI: 1.5-1.8) months and the median overall survival (OS) was 3.6 (95% CI: 2.7-not reached) months. One response-inevaluable patient achieved clinical stability for 5 months with reduction in CA19-9 and ctDNA levels with a MAP2K1 treatment resistance mutation detected in ctDNA at clinical progression.
    Conclusions: The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC.
    Keywords:  FAK inhibition; GSK2256098; MEK inhibition; Pancreatic adenocarcinoma (PDAC); trametinib
    DOI:  https://doi.org/10.21037/jgo-22-86
  14. Cell Rep. 2022 Dec 29. pii: S2211-1247(22)01835-6. [Epub ahead of print]42(1): 111934
    Progressive development of melanoma-induced cachexia differentially impacts organ systems in mice.
    Flavia A Graca, Anna Stephan, Yong-Dong Wang, Abbas Shirinifard, Jianqin Jiao, Peter Vogel, Myriam Labelle, Fabio Demontis.
      Cachexia is a systemic wasting syndrome that increases cancer-associated mortality. How cachexia progressively and differentially impacts distinct tissues is largely unknown. Here, we find that the heart and skeletal muscle undergo wasting at early stages and are the tissues transcriptionally most impacted by cachexia. We also identify general and organ-specific transcriptional changes that indicate functional derangement by cachexia even in tissues that do not undergo wasting, such as the brain. Secreted factors constitute a top category of cancer-regulated genes in host tissues, and these changes include upregulation of the angiotensin-converting enzyme (ACE). ACE inhibition with the drug lisinopril improves muscle force and partially impedes cachexia-induced transcriptional changes, although wasting is not prevented, suggesting that cancer-induced host-secreted factors can regulate tissue function during cachexia. Altogether, by defining prevalent and temporal and tissue-specific responses to cachexia, this resource highlights biomarkers and possible targets for general and tissue-tailored anti-cachexia therapies.
    Keywords:  ACE inhibitor; CP: Cancer; angiotensin-converting enzyme; cachexia-modulated secreted factors; cancer cachexia; cancer progression; lisinopril; myokine; pediatric melanoma xenografts; skeletal muscle dysfunction; wasting
    DOI:  https://doi.org/10.1016/j.celrep.2022.111934
  15. Autophagy. 2023 Jan 10.
    Where is the field of autophagy research heading?
    Hagai Abeliovich, Jayanta Debnath, Wen-Xing Ding, William T Jackson, Do-Hyung Kim, Daniel J Klionsky, Nicholas Ktistakis, Marta Margeta, Christian Münz, Morten Petersen, Junichi Sadoshima, Isabelle Vergne.
      In this editors' corner, the section editors were asked to indicate where they see the autophagy field heading and to suggest what they consider to be key unanswered questions in their specialty area.
    Keywords:  Ideas for your grant proposal; suggestions; the big picture; the grand scheme; thoughts; yada yada yada
    DOI:  https://doi.org/10.1080/15548627.2023.2166301
  16. Nat Rev Cancer. 2023 Jan 10.
    RNA splicing dysregulation and the hallmarks of cancer.
    Robert K Bradley, Olga Anczuków.
      Dysregulated RNA splicing is a molecular feature that characterizes almost all tumour types. Cancer-associated splicing alterations arise from both recurrent mutations and altered expression of trans-acting factors governing splicing catalysis and regulation. Cancer-associated splicing dysregulation can promote tumorigenesis via diverse mechanisms, contributing to increased cell proliferation, decreased apoptosis, enhanced migration and metastatic potential, resistance to chemotherapy and evasion of immune surveillance. Recent studies have identified specific cancer-associated isoforms that play critical roles in cancer cell transformation and growth and demonstrated the therapeutic benefits of correcting or otherwise antagonizing such cancer-associated mRNA isoforms. Clinical-grade small molecules that modulate or inhibit RNA splicing have similarly been developed as promising anticancer therapeutics. Here, we review splicing alterations characteristic of cancer cell transcriptomes, dysregulated splicing's contributions to tumour initiation and progression, and existing and emerging approaches for targeting splicing for cancer therapy. Finally, we discuss the outstanding questions and challenges that must be addressed to translate these findings into the clinic.
    DOI:  https://doi.org/10.1038/s41568-022-00541-7
  17. STAR Protoc. 2023 Jan 12. pii: S2666-1667(22)00902-9. [Epub ahead of print]4(1): 102022
    Optimized protocol for the generation of an orthotopic colon cancer mouse model and metastasis.
    Sophie Richon, Olivier Zajac, Carlos Perez Gonzalez, Danijela Matic Vignjevic.
      The microenvironment plays an essential role in tumor development and metastatic progression. Here, we describe a simple and rapid protocol to generate tumors in mice using colon cancer cell lines or tumoroids in the correct microenvironment, colonic mucosa. We also detail steps for monitoring the growth of the primary tumor in real time using colonoscopy or in vivo imaging system, as well as monitoring metastasis development. Finally, we describe tissue collection and sample preparation for subsequent immunohistochemistry analysis.
    Keywords:  Cancer; Cell Biology; Health Sciences; Microscopy; Model Organisms; Organoids
    DOI:  https://doi.org/10.1016/j.xpro.2022.102022
  18. Mol Cell. 2023 Jan 06. pii: S1097-2765(22)01202-3. [Epub ahead of print]
    p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression.
    Monisankar Ghosh, Suchandrima Saha, Jinyu Li, David C Montrose, Luis A Martinez.
      Tumor suppression by TP53 involves cell-autonomous and non-cell-autonomous mechanisms. TP53 can suppress tumor growth by modulating immune system functions; however, the mechanistic basis for this activity is not well understood. We report that p53 promotes the degradation of the DNA exonuclease TREX1, resulting in cytosolic dsDNA accumulation. We demonstrate that p53 requires the ubiquitin ligase TRIM24 to induce TREX1 degradation. The cytosolic DNA accumulation resulting from TREX1 degradation activates the cytosolic DNA-sensing cGAS/STING pathway, resulting in induction of type I interferons. TREX1 overexpression sufficed to block p53 activation of the cGAS/STING pathway. p53-mediated induction of type I interferon (IFNB1) is suppressed by cGAS/STING knockout, and p53's tumor suppressor activities are compromised by the loss of signaling through the cGAS/STING pathway. Thus, our study reveals that p53 utilizes the cGAS/STING innate immune system pathway for both cell-intrinsic and cell-extrinsic tumor suppressor activities.
    Keywords:  STING; TREX1; cGAS; innate immunity; p53; tumor suppression
    DOI:  https://doi.org/10.1016/j.molcel.2022.12.023
  19. Cancers (Basel). 2022 Dec 28. pii: 191. [Epub ahead of print]15(1):
    The CAM Model-Q&A with Experts.
    Dagmar Fischer, Georg Fluegen, Paul Garcia, Nassim Ghaffari-Tabrizi-Wizsy, Laura Gribaldo, Ruby Yun-Ju Huang, Volker Rasche, Domenico Ribatti, Xavier Rousset, Marta Texeira Pinto, Jean Viallet, Yan Wang, Regine Schneider-Stock.
      The chick chorioallantoic membrane (CAM), as an extraembryonic tissue layer generated by the fusion of the chorion with the vascularized allantoic membrane, is easily accessible for manipulation. Indeed, grafting tumor cells on the CAM lets xenografts/ovografts develop in a few days for further investigations. Thus, the CAM model represents an alternative test system that is a simple, fast, and low-cost tool to study tumor growth, drug response, or angiogenesis in vivo. Recently, a new era for the CAM model in immune-oncology-based drug discovery has been opened up. Although there are many advantages offering extraordinary and unique applications in cancer research, it has also disadvantages and limitations. This review will discuss the pros and cons with experts in the field.
    Keywords:  angiogenesis model; drug discovery; immune-oncology; metastasis model; personalized therapy; standard operation procedures; tumor growth
    DOI:  https://doi.org/10.3390/cancers15010191
  20. Nature. 2023 Jan 12.
    Targeting TBK1 to overcome resistance to cancer immunotherapy.
    Yi Sun, Or-Yam Revach, Seth Anderson, Emily A Kessler, Clara H Wolfe, Anne Jenney, Caitlin E Mills, Emily J Robitschek, Thomas G R Davis, Sarah Kim, Amina Fu, Xiang Ma, Jia Gwee, Payal Tiwari, Peter P Du, Princy Sindurakar, Jun Tian, Arnav Mehta, Alexis M Schneider, Keren Yizhak, Moshe Sade-Feldman, Thomas LaSalle, Tatyana Sharova, Hongyan Xie, Shuming Liu, William A Michaud, Rodrigo Saad-Beretta, Kathleen B Yates, Arvin Iracheta-Vellve, Johan K E Spetz, Xingping Qin, Kristopher A Sarosiek, Gao Zhang, Jong Wook Kim, Mack Y Su, Angelina M Cicerchia, Martin Q Rasmussen, Samuel J Klempner, Dejan Juric, Sara I Pai, David M Miller, Anita Giobbie-Hurder, Jonathan H Chen, Karin Pelka, Dennie T Frederick, Susanna Stinson, Elena Ivanova, Amir R Aref, Cloud P Paweletz, David A Barbie, Debattama R Sen, David E Fisher, Ryan B Corcoran, Nir Hacohen, Peter K Sorger, Keith T Flaherty, Genevieve M Boland, Robert T Manguso, Russell W Jenkins.
      Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking1,2. We identified the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune evasion gene in a pooled genetic screen4. Using a suite of genetic and pharmacologic tools across multiple experimental model systems, we confirm a role for TBK1 as an immune evasion gene. Targeting TBK1 enhances response to PD-1 blockade by lowering the cytotoxicity threshold to effector cytokines (TNFα/IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids (PDOTS) and matched patient-derived organoids (PDOs). Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNFα/IFNγ in a JAK/STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-023-05704-6
  21. Nat Med. 2023 Jan 09.
    Multistain deep learning for prediction of prognosis and therapy response in colorectal cancer.
    Sebastian Foersch, Christina Glasner, Ann-Christin Woerl, Markus Eckstein, Daniel-Christoph Wagner, Stefan Schulz, Franziska Kellers, Aurélie Fernandez, Konstantina Tserea, Michael Kloth, Arndt Hartmann, Achim Heintz, Wilko Weichert, Wilfried Roth, Carol Geppert, Jakob Nikolas Kather, Moritz Jesinghaus.
      Although it has long been known that the immune cell composition has a strong prognostic and predictive value in colorectal cancer (CRC), scoring systems such as the immunoscore (IS) or quantification of intraepithelial lymphocytes are only slowly being adopted into clinical routine use and have their limitations. To address this we established and evaluated a multistain deep learning model (MSDLM) utilizing artificial intelligence (AI) to determine the AImmunoscore (AIS) in more than 1,000 patients with CRC. Our model had high prognostic capabilities and outperformed other clinical, molecular and immune cell-based parameters. It could also be used to predict the response to neoadjuvant therapy in patients with rectal cancer. Using an explainable AI approach, we confirmed that the MSDLM's decisions were based on established cellular patterns of anti-tumor immunity. Hence, the AIS could provide clinicians with a valuable decision-making tool based on the tumor immune microenvironment.
    DOI:  https://doi.org/10.1038/s41591-022-02134-1
  22. Cancer Cell. 2023 Jan 03. pii: S1535-6108(22)00594-3. [Epub ahead of print]
    Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy.
    Gaopeng Li, Jae Eun Choi, Ilona Kryczek, Yilun Sun, Peng Liao, Shasha Li, Shuang Wei, Sara Grove, Linda Vatan, Reagan Nelson, Grace Schaefer, Steven G Allen, Kamya Sankar, Leslie A Fecher, Mishal Mendiratta-Lala, Timothy L Frankel, Angel Qin, Jessica J Waninger, Alangoya Tezel, Ajjai Alva, Christopher D Lao, Nithya Ramnath, Marcin Cieslik, Paul W Harms, Michael D Green, Arul M Chinnaiyan, Weiping Zou.
      Immune checkpoint blockade (ICB) can produce durable responses against cancer. We and others have found that a subset of patients experiences paradoxical rapid cancer progression during immunotherapy. It is poorly understood how tumors can accelerate their progression during ICB. In some preclinical models, ICB causes hyperprogressive disease (HPD). While immune exclusion drives resistance to ICB, counterintuitively, patients with HPD and complete response (CR) following ICB manifest comparable levels of tumor-infiltrating CD8+ T cells and interferon γ (IFNγ) gene signature. Interestingly, patients with HPD but not CR exhibit elevated tumoral fibroblast growth factor 2 (FGF2) and β-catenin signaling. In animal models, T cell-derived IFNγ promotes tumor FGF2 signaling, thereby suppressing PKM2 activity and decreasing NAD+, resulting in reduction of SIRT1-mediated β-catenin deacetylation and enhanced β-catenin acetylation, consequently reprograming tumor stemness. Targeting the IFNγ-PKM2-β-catenin axis prevents HPD in preclinical models. Thus, the crosstalk of core immunogenic, metabolic, and oncogenic pathways via the IFNγ-PKM2-β-catenin cascade underlies ICB-associated HPD.
    Keywords:  FGF2; IFNγ; PD-L1/PD-1 pathway; T cell immunity; complete response; glycolytic metabolism; hyperprogressive disease; immune checkpoint blockade; oncogenesis; β-catenin
    DOI:  https://doi.org/10.1016/j.ccell.2022.12.008
  23. Cell. 2023 Jan 09. pii: S0092-8674(22)01570-7. [Epub ahead of print]
    Loss of epigenetic information as a cause of mammalian aging.
    Jae-Hyun Yang, Motoshi Hayano, Patrick T Griffin, João A Amorim, Michael S Bonkowski, John K Apostolides, Elias L Salfati, Marco Blanchette, Elizabeth M Munding, Mital Bhakta, Yap Ching Chew, Wei Guo, Xiaojing Yang, Sun Maybury-Lewis, Xiao Tian, Jaime M Ross, Giuseppe Coppotelli, Margarita V Meer, Ryan Rogers-Hammond, Daniel L Vera, Yuancheng Ryan Lu, Jeffrey W Pippin, Michael L Creswell, Zhixun Dou, Caiyue Xu, Sarah J Mitchell, Abhirup Das, Brendan L O'Connell, Sachin Thakur, Alice E Kane, Qiao Su, Yasuaki Mohri, Emi K Nishimura, Laura Schaevitz, Neha Garg, Ana-Maria Balta, Meghan A Rego, Meredith Gregory-Ksander, Tatjana C Jakobs, Lei Zhong, Hiroko Wakimoto, Jihad El Andari, Dirk Grimm, Raul Mostoslavsky, Amy J Wagers, Kazuo Tsubota, Stephen J Bonasera, Carlos M Palmeira, Jonathan G Seidman, Christine E Seidman, Norman S Wolf, Jill A Kreiling, John M Sedivy, George F Murphy, Richard E Green, Benjamin A Garcia, Shelley L Berger, Philipp Oberdoerffer, Stuart J Shankland, Vadim N Gladyshev, Bruce R Ksander, Andreas R Pfenning, Luis A Rajman, David A Sinclair.
      All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.
    Keywords:  DNA damage; RCM; aging; chromatin; epigenetic clock; epigenetic reprogramming; relocalization of chromatin modifier; senescence
    DOI:  https://doi.org/10.1016/j.cell.2022.12.027
  24. J Biol Chem. 2023 Jan 06. pii: S0021-9258(23)00010-8. [Epub ahead of print] 102878
    Overexpression of Pdx1, reduction of p53, or deletion of CHOP attenuates pancreas hypoplasia in mice with pancreas-specific O-GlcNAc Transferase deletion.
    Alicia Wong, Samantha Pritchard, Mackenzie Moore, Brian Akhaphong, Nandini Avula, Megan Beetch, Yoshio Fujitani, Emilyn U Alejandro.
      Deletion of O-GlcNAc Transferase (Ogt) in pancreatic epithelial progenitor cells results in pancreatic hypoplasia at birth, partly due to increased apoptosis during embryonic development. Constitutive loss of Ogt in β-cells results in increased ER stress and apoptosis, and in the Ogt-deficient pancreas, transcriptomic data previously revealed tumor suppressor protein p53 and pancreatic and duodenal homeobox 1 (Pdx1), key cell survival proteins in the developing pancreas, as upstream regulators of differentially expressed genes. However, the specific roles of these genes in pancreatic hypoplasia are unclear. In this study, we explored the independent roles of p53, ER stress protein CHOP, and Pdx1 in pancreas development and their use in the functional rescue of pancreatic hypoplasia in the context of Ogt loss. Using in vivo genetic manipulation and morphometric analysis, we show that Ogt plays a key regulatory role in pancreas development. We demonstrate heterozygous but not homozygous loss of pancreatic p53 afforded partial rescue of β-cell, α-cell, and exocrine cell masses while whole-body loss of CHOP afforded a partial rescue in pancreas weight and a full rescue in exocrine cell mass. However, neither were sufficient to mitigate pancreatic hypoplasia at birth in the Ogt-deficient pancreas. Furthermore, overexpression of Pdx1 in the pancreatic epithelium resulted in partial rescues in pancreas weight and β-cell mass in the Ogt loss background. These findings highlight the requirement of Ogt in pancreas development by targeting multiple proteins such as transcription factor Pdx1 and p53 in the developing pancreas.
    DOI:  https://doi.org/10.1016/j.jbc.2023.102878
  25. Autophagy. 2023 Jan 12. 1-11
    Sensitive imaging of Endoplasmic reticulum (ER) autophagy with an acidity-reporting ER-Tracker.
    Yilong Shi, Xiaoxue Zou, Xianghui Zheng, Yimin Wu, Jiahuai Han, Shoufa Han.
      Macroautophagic/autophagic turnover of endoplasmic reticulum (reticulophagy) is critical for cell health. Herein we reported a sensitive fluorescence-on imaging of reticulophagy using a small molecule probe (ER-proRed) comprised of green-emissive fluorinated rhodol for ER targeting and nonfluorescent rhodamine-lactam prone to lysosome-triggered red fluorescence. Partitioned in ER to exhibit green fluorescence, ER-proRed gives intense red fluorescence upon co-delivery with ER into acidic lysosomes. Serving as the signal of reticulophagy, the turning on of red fluorescence enables discernment of reticulophagy induced by starvation, varied levels of reticulophagic receptors, and chemical agents such as etoposide and sodium butyrate. These results show ER probes optically activatable in lysosomes, such as ER-proRed, offer a sensitive and simplified tool for studying reticulophagy in biology and diseases.Abbreviations: Baf-A1, bafilomycin A1; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; CQ, chloroquine diphosphate; ER, endoplasmic reticulum; FHR, fluorinated hydrophobic rhodol; GFP, green fluorescent protein; Reticulophagy, selective autophagy of ER; RFP, red fluorescent protein; ROX, X-rhodamine; UPR, unfolded protein response.
    Keywords:  Autophagy imaging; endoplasmic reticulum; fluorescence-on; lysosomal acidity; reticulophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2165759
  26. Oncogene. 2023 Jan 09.
    Muc4 loss mitigates epidermal growth factor receptor activity essential for PDAC tumorigenesis.
    Rakesh Bhatia, Jawed Akhtar Siddiqui, Koelina Ganguly, Christopher M Thompson, Andrew Cannon, Abhijit Aithal, Naveenkumar Perumal, Shailendra K Maurya, Xiaoqi Li, Jesse L Cox, Channabasavaiah B Gurumurthy, Satyanarayana Rachagani, Maneesh Jain, Mohd Wasim Nasser, Surinder K Batra, Sushil Kumar.
      Mucin4 (MUC4) appears early during pancreatic intraepithelial neoplasia-1 (PanIN1), coinciding with the expression of epidermal growth factor receptor-1 (EGFR). The EGFR signaling is required for the onset of Kras-driven pancreatic ductal adenocarcinoma (PDAC); however, the players and mechanisms involved in sustained EGFR signaling in early PanIN lesions remain elusive. We generated a unique Esai-CRISPR-based Muc4 conditional knockout murine model to evaluate its effect on PDAC pathology. The Muc4 depletion in the autochthonous murine model carrying K-ras and p53 mutations (K-rasG12D; TP53R172H; Pdx-1cre, KPC) to generate the KPCM4-/- murine model showed a significant delay in the PanIN lesion formation with a significant reduction (p < 0.01) in EGFR (Y1068) and ERK1/2 (T202/Y204) phosphorylation. Further, a significant decrease (p < 0.01) in Sox9 expression in PanIN lesions of KPCM4-/- mice suggested the impairment of acinar-to-ductal metaplasia in Muc4-depleted cells. The biochemical analyses demonstrated that MUC4, through its juxtamembrane EGF-like domains, interacts with the EGFR ectodomain, and its cytoplasmic tail prevents EGFR ubiquitination and subsequent proteasomal degradation upon ligand stimulation, leading to sustained downstream oncogenic signaling. Targeting the MUC4 and EGFR interacting interface provides a promising strategy to improve the efficacy of EGFR-targeted therapies in PDAC and other MUC4-expressing malignancies.
    DOI:  https://doi.org/10.1038/s41388-022-02587-1
  27. Nat Rev Clin Oncol. 2023 Jan 12.
    Humanized mouse models for immuno-oncology research.
    Jane Chuprin, Hannah Buettner, Mina O Seedhom, Dale L Greiner, James G Keck, Fumihiko Ishikawa, Leonard D Shultz, Michael A Brehm.
      Immunotherapy has emerged as a promising treatment paradigm for many malignancies and is transforming the drug development landscape. Although immunotherapeutic agents have demonstrated clinical efficacy, they are associated with variable clinical responses, and substantial gaps remain in our understanding of their mechanisms of action and specific biomarkers of response. Currently, the number of preclinical models that faithfully recapitulate interactions between the human immune system and tumours and enable evaluation of human-specific immunotherapies in vivo is limited. Humanized mice, a term that refers to immunodeficient mice co-engrafted with human tumours and immune components, provide several advantages for immuno-oncology research. In this Review, we discuss the benefits and challenges of the currently available humanized mice, including specific interactions between engrafted human tumours and immune components, the development and survival of human innate immune populations in these mice, and approaches to study mice engrafted with matched patient tumours and immune cells. We highlight the latest advances in the generation of humanized mouse models, with the aim of providing a guide for their application to immuno-oncology studies with potential for clinical translation.
    DOI:  https://doi.org/10.1038/s41571-022-00721-2
  28. Trends Cancer. 2023 Jan 11. pii: S2405-8033(22)00265-5. [Epub ahead of print]
    Addressing the genetic/nongenetic duality in cancer with systems biology.
    Prakash Kulkarni, H Steven Wiley, Herbert Levine, Herbert Sauro, Alexander Anderson, Stephen T C Wong, Aaron S Meyer, Puneeth Iyengar, Kevin Corlette, Kristin Swanson, Atish Mohanty, Supriyo Bhattacharya, Amit Patel, Vinay Jain, Ravi Salgia.
      The dogma that cancer is a genetic disease is being questioned. Recent findings suggest that genetic/nongenetic duality is necessary for cancer progression. A think tank organized by the Shraman Foundation's Institute for Theoretical Biology compiled key challenges and opportunities that theoreticians, experimentalists, and clinicians can explore from a systems biology perspective to provide a better understanding of the disease as well as help discover new treatment options and therapeutic strategies.
    DOI:  https://doi.org/10.1016/j.trecan.2022.12.004
  29. Front Aging Neurosci. 2022 ;14 1042488
    Biological age and environmental risk factors for dementia and stroke: Molecular mechanisms.
    Pablo Knobel, Rachel Litke, Charles V Mobbs.
      Since the development of antibiotics and vaccination, as well as major improvements in public hygiene, the main risk factors for morbidity and mortality are age and chronic exposure to environmental factors, both of which can interact with genetic predispositions. As the average age of the population increases, the prevalence and costs of chronic diseases, especially neurological conditions, are rapidly increasing. The deleterious effects of age and environmental risk factors, develop chronically over relatively long periods of time, in contrast to the relatively rapid deleterious effects of infectious diseases or accidents. Of particular interest is the hypothesis that the deleterious effects of environmental factors may be mediated by acceleration of biological age. This hypothesis is supported by evidence that dietary restriction, which universally delays age-related diseases, also ameliorates deleterious effects of environmental factors. Conversely, both age and environmental risk factors are associated with the accumulation of somatic mutations in mitotic cells and epigenetic modifications that are a measure of "biological age", a better predictor of age-related morbidity and mortality than chronological age. Here we review evidence that environmental risk factors such as smoking and air pollution may also drive neurological conditions, including Alzheimer's Disease, by the acceleration of biological age, mediated by cumulative and persistent epigenetic effects as well as somatic mutations. Elucidation of such mechanisms could plausibly allow the development of interventions which delay deleterious effects of both aging and environmental risk factors.
    Keywords:  aging; dementia; environmental risk factors; epigenetic effects; stroke
    DOI:  https://doi.org/10.3389/fnagi.2022.1042488
  30. J Control Release. 2023 Jan 07. pii: S0168-3659(23)00010-X. [Epub ahead of print]
    A biomimetic nanodrug for enhanced chemotherapy of pancreatic tumors.
    Fu Zhang, Qida Hu, Bowen Li, Yong Huang, Meng Wang, Shiyi Shao, Honglin Tang, Zhuo Yao, Yuan Ping, Tingbo Liang.
      Pancreatic ductal adenocarcinoma (PDAC) remains to be one of the highest malignant tumors due to its poor chemotherapeutic efficacy and multidrug resistance. A major reason for the failure in chemotherapy is poor drug accumulation into PDAC tumor tissues due to the overexpressed extracellular matrix (ECM) stroma, which forms a major obstacle limiting the deep tissue penetration of chemotherapeutics. Herein, we report a tumor microenvironment (TME)-responsive nanodrug, based on PDAC cell membrane-coated gold nanocages (AuNCs), to co-deliver the chemotherapeutics (GEM) and nitrogen oxide (NO) donor (L-Arg) to enhance drug accumulation and reduce chemoresistance. The high glutathione (GSH) level can trigger the cleavage of the disulfide bond on nanodrug to release GEM. Moreover, the elevated ROS level could activate L-Arg to generate NO, which synergistically facilitate GEM to penetrate into deep tissues by means of vasodilation and normalization of blood vessels in the PDAC tumor tissue. In addition, AuNCs not only serve as a photothermal agent for chemotherapy, but also generate photoacoustic signals to monitor drug accumulation and distribution. As expected, the strategy demonstrates to be remarkable in treating different xenograft mice models, especially in orthotopic and patient-derived xenograft (PDX) models. The current study defines a useful therapeutic tool for treating PDAC tumors.
    Keywords:  Gas therapy; Gemcitabine chemotherapy; Gold nanocages; Pancreatic cancer; Photoacoustic tomography
    DOI:  https://doi.org/10.1016/j.jconrel.2023.01.007
  31. Biophys J. 2023 Jan 12. pii: S0006-3495(23)00027-9. [Epub ahead of print]
    Cell size and actin architecture determine force generation in optogenetically activated cells.
    T Andersen, D Wörthmüller, D Probst, I Wang, P Moreau, V Fitzpatrick, T Boudou, U S Schwarz, M Balland.
      Adherent cells use actomyosin contractility to generate mechanical force and to sense the physical properties of their environment, with dramatic consequences for migration, division, differentiation and fate. However, the organization of the actomyosin system within cells is highly variable, with its assembly and function being controlled by small GTPases from the Rho-family. In order to understand better how activation of these regulators translates into cell-scale force generation in the context of different physical environments, here we combine recent advances in non-neuronal optogenetics with micropatterning and traction force microscopy on soft elastic substrates. We find that after whole-cell RhoA-activation by the CRY2/CIBN optogenetic system with a short pulse of 100 milliseconds, single cells contract on minute time scale in proportion to their original traction force, before returning to their original tension setpoint with near perfect precision, on a longer time scale of several minutes. To decouple the biochemical and mechanical elements of this response, we introduce a mathematical model that is parametrized by fits to the dynamics of the substrate deformation energy. We find that the RhoA-response builds up quickly on a time scale of 20 seconds, but decays slowly on a time scale of 50 seconds. The larger the cells and the more polarized their actin cytoskeleton, the more substrate deformation energy is generated. RhoA-activation starts to saturate if optogenetic pulse length exceeds 50 milliseconds, revealing the intrinsic limits of biochemical activation. Together our results suggest that adherent cells establish tensional homeostasis by the RhoA-system, but that the setpoint and the dynamics around it are strongly determined by cell size and the architecture of the actin cytoskeleton, which both are controlled by the extracellular environment.
    DOI:  https://doi.org/10.1016/j.bpj.2023.01.011
  32. Sci Signal. 2023 Jan 10. 16(767): eadg2868
    Seeing is great, understanding is better.
    H Holden Thorp, Michael B Yaffe.
      In January 2008, the journal and knowledge environment Science's STKE was renamed Science Signaling, and primary research papers were first published later that year. To mark this anniversary, Thorp and Yaffe reflect on the importance of basic research to scientific progress.
    DOI:  https://doi.org/10.1126/scisignal.adg2868
  33. ACS Sens. 2023 Jan 06.
    Mechanosensitive Channel-Based Optical Membrane Tension Reporter.
    Yen-Yu Hsu, Agnes M Resto Irizarry, Jianping Fu, Allen P Liu.
      Plasma membrane tension functions as a global physical organizer of cellular activities. Technical limitations of current membrane tension measurement techniques have hampered in-depth investigation of cellular membrane biophysics and the role of plasma membrane tension in regulating cellular processes. Here, we develop an optical membrane tension reporter by repurposing an E. coli mechanosensitive channel via insertion of circularly permuted GFP (cpGFP), which undergoes a large conformational rearrangement associated with channel activation and thus fluorescence intensity changes under increased membrane tension.
    Keywords:  cell mechanics; mechanosensitive channel; membrane tension; protein engineering; reporter
    DOI:  https://doi.org/10.1021/acssensors.2c01921
  34. Dis Model Mech. 2023 Jan 01. pii: dmm049729. [Epub ahead of print]16(1):
    Understanding and modeling nerve-cancer interactions.
    Thanh T Le, Madeleine J Oudin.
      The peripheral nervous system plays an important role in cancer progression. Studies in multiple cancer types have shown that higher intratumoral nerve density is associated with poor outcomes. Peripheral nerves have been shown to directly regulate tumor cell properties, such as growth and metastasis, as well as affect the local environment by modulating angiogenesis and the immune system. In this Review, we discuss the identity of nerves in organs in the periphery where solid tumors grow, the known mechanisms by which nerve density increases in tumors, and the effects these nerves have on cancer progression. We also discuss the strengths and weaknesses of current in vitro and in vivo models used to study nerve-cancer interactions. Increased understanding of the mechanisms by which nerves impact tumor progression and the development of new approaches to study nerve-cancer interactions will facilitate the discovery of novel treatment strategies to treat cancer by targeting nerves.
    Keywords:  Cancer; Innervation; Models
    DOI:  https://doi.org/10.1242/dmm.049729
  35. Am J Cancer Res. 2022 ;12(12): 5668-5683
    Prognostic implications of microRNA-21 overexpression in pancreatic ductal adenocarcinoma: an international multicenter study of 686 patients.
    Asif Ali, Nigel Balfour Jamieson, Ishaq N Khan, David Chang, Elisa Giovannetti, Nicola Funel, Adam E Frampton, Jennifer Morton, Owen Sansom, Thomas R Jeffry Evans, Fraser Duthie, Colin J McKay, Jas Samra, Anthony J Gill, Andrew Biankin, Karin A Oien.
      Despite progress in genomic characterization, no single prognostic marker that can be evaluated using an easy-to-perform and relatively inexpensive method is available for pancreatic ductal adenocarcinoma (PDAC). MicroRNAs, which are stable, tumor- and tissue-specific molecules, are potentially ideal biomarkers, and we established an inter-laboratory validated method to investigate miR-21 as a prognostic biomarker in PDAC. The study samples of PDAC patients were recruited from a test cohort of Glasgow (n = 189) and three validation cohorts of Pisa (n = 69), Sydney (n = 249), and International Cancer Genome Consortium (ICGC) (n = 249). Tissue microarrays were used for miR-21 staining by chromogenic in situ hybridization (CISH). The patients were subdivided into no/low and high miR-21 staining groups using a specific histoscore. Furthermore, miR-21 staining was evaluated against clinicopathological variables and follow-up data by Fisher/log-rank test and Cox proportional models. The prognostic variables found to be significant in univariate analysis (P value < 0.10) were included in multivariate analysis in a backward-stepwise fashion. MiR-21 expression was cytoplasmic, with more consistent staining in the malignant ductal epithelium than in the stroma. The expression of miR-21 was significantly associated with tumor size and lymph node metastasis, whereas no association was observed with other clinicopathological variables. High miR-21 staining (histoscore ≥ 45 [median score]) was an independent predictor of survival in the Glasgow test cohort (HR 2.37, 95% CI: 1.42-3.96, P < 0.0001) and three validation cohorts (Pisa, HR 2.03, 95% CI: 1.21-3.39, P = 0.007; Sydney, HR 2.58, 95% CI (1.21-3.39), P < 0.0001; and ICGC, HR 3.34, 95% CI: 2.07-5.84, P = 0.002) when adjusted for clinical variables in a multivariate model. In comparison to the patients with low miR-21, the patients with high miR-21 expression had significant increase in OS as they benefit from gemcitabine-based adjuvant chemotherapy (Glasgow 16.5 months [with chemotherapy] vs 10.5 months [without chemotherapy]); Sydney 25.0 vs 10.6; ICGC 25.2 vs 11.9. These results indicated that miR-21 is a predictor of survival, prompting prospective trials. Evaluation of miR-21 offers new opportunities for the stratification of patients with PDAC and might facilitate the implementation of clinical management and therapeutic interventions for this devastating disease.
    Keywords:  MiR-21; Pancreatic ductal adenocarcinoma; chromogenic in-situ hybridization; gemcitabine adjuvant chemotherapy; overall survival; prognosis; tissue microarrays
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