bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023–03–05
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. COL11A1-driven positive feedback loop modulates fibroblast transformation and activates pancreatic cancer progression.
  2. GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1.
  3. mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion.
  4. CD39/CD73/A2AR pathway and cancer immunotherapy.
  5. Interplay Between Extracellular Matrix Remodeling and Angiogenesis in Tumor Ecosystem.
  6. Multiple myeloma cell-derived exosomes promote tumor favorable functional performance by polarization of macrophages toward M2 like cells.
  7. Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity.
  1. Cell Biol Int. 2023 Mar 02.
    COL11A1-driven positive feedback loop modulates fibroblast transformation and activates pancreatic cancer progression.
    Defeng Sun, Tu Dai, Yuan Ji, Weibo Shen, Wuyang Bian.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most common leading causes of cancer death. The cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) aggravate the malignant behavior of PDAC. However, it is still unknown how PDAC induces normal fibroblasts (NFs) to CAFs. In present research, we found that PDAC-derived collagen type XI alpha 1 (COL11A1) promoted the conversion of NFs to CAF-like cells. It included morphological and corresponding molecular marker changes. Activation of the nuclear factor-κB (NF-κB) pathway was involved in this process. Corresponding, CAFs cells could secrete interleukin 6 (IL-6), which promoted the invasion and the epithelial-mesenchymal transition of PDAC cells. Furthermore, IL-6 promoted the expression of transcription factor Activating Transcription Factor 4 by activating the Mitogen-Activated Protein Kinase/extracellular-signal-regulated kinase pathway. The latter directly promotes the expression of COL11A1. This way, a feedback loop of mutual influence was constructed between PDAC and CAFs. Our research proposed a novel concept for PDAC-educated NFs. PDAC-COL11A1-fibroblast-IL-6-PDAC axis might contribute to the cascade between PDAC and TME.
    Keywords:  CAFs; COL11A1; IL-6; PDAC; TME
    DOI:  https://doi.org/10.1002/cbin.12009
  2. Biochim Biophys Acta Gene Regul Mech. 2023 Feb 24. pii: S1874-9399(23)00019-6. [Epub ahead of print] 194924
    GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1.
    Luciana L Almada, Kim Barroso, Sandhya Sen, Murat Toruner, Ashley N Sigafoos, Glancis L Raja Arul, David R Pease, Renzo E Vera, Rachel L O Olson, Holger W Auner, Rémy Pedeux, Juan L Iovanna, Eric Chevet, Martin E Fernandez-Zapico.
      Upon accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER), the Unfolded Protein Response (UPR) is triggered to restore ER homeostasis. The induction of stress genes is a sine qua non condition for effective adaptive UPR. Although this requirement has been extensively described, the mechanisms underlying this process remain in part uncharacterized. Here, we show that p97/VCP, an AAA+ ATPase known to contribute to ER stress-induced gene expression, regulates the transcription factor GLI1, a primary effector of Hedgehog (Hh) signaling. Under basal (non-ER stress) conditions, GLI1 is repressed by a p97/VCP-HDAC1 complex while upon ER stress GLI1 is induced through a mechanism requiring both USF2 binding and increase histone acetylation at its promoter. Interestingly, the induction of GLI1 was independent of ligand-regulated Hh signaling. Further analysis showed that GLI1 cooperates with ATF6f to induce promoter activity and expression of XBP1, a key transcription factor driving UPR. Overall, our work demonstrates a novel role for GLI1 in the regulation of ER stress gene expression and defines the interplay between p97/VCP, HDAC1 and USF2 as essential players in this process.
    Keywords:  ER stress; GLI1; HDAC1; Hedgehog; UPR; USF2; p97/VCP
    DOI:  https://doi.org/10.1016/j.bbagrm.2023.194924
  3. Nat Commun. 2023 Mar 03. 14(1): 1214
    mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion.
    Heng-Jia Liu, Heng Du, Damir Khabibullin, Mahsa Zarei, Kevin Wei, Gordon J Freeman, David J Kwiatkowski, Elizabeth P Henske.
      Identifying the mechanisms underlying the regulation of immune checkpoint molecules and the therapeutic impact of targeting them in cancer is critical. Here we show that high expression of the immune checkpoint B7-H3 (CD276) and high mTORC1 activity correlate with immunosuppressive phenotypes and worse clinical outcomes in 11,060 TCGA human tumors. We find that mTORC1 upregulates B7-H3 expression via direct phosphorylation of the transcription factor YY2 by p70 S6 kinase. Inhibition of B7-H3 suppresses mTORC1-hyperactive tumor growth via an immune-mediated mechanism involving increased T-cell activity and IFN-γ responses coupled with increased tumor cell expression of MHC-II. CITE-seq reveals strikingly increased cytotoxic CD38+CD39+CD4+ T cells in B7-H3-deficient tumors. In pan-human cancers, a high cytotoxic CD38+CD39+CD4+ T-cell gene signature correlates with better clinical prognosis. These results show that mTORC1-hyperactivity, present in many human tumors including tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), drives B7-H3 expression leading to suppression of cytotoxic CD4+ T cells.
    DOI:  https://doi.org/10.1038/s41467-023-36881-7
  4. Mol Cancer. 2023 03 02. 22(1): 44
    CD39/CD73/A2AR pathway and cancer immunotherapy.
    Chenglai Xia, Shuanghong Yin, Kenneth K W To, Liwu Fu.
      Cancer development is closely associated with immunosuppressive tumor microenvironment (TME) that attenuates antitumor immune responses and promotes tumor cell immunologic escape. The sequential conversion of extracellular ATP into adenosine by two important cell-surface ectonucleosidases CD39 and CD73 play critical roles in reshaping an immunosuppressive TME. The accumulated extracellular adenosine mediates its regulatory functions by binding to one of four adenosine receptors (A1R, A2AR, A2BR and A3R). The A2AR elicits its profound immunosuppressive function via regulating cAMP signaling. The increasing evidence suggests that CD39, CD73 and A2AR could be used as novel therapeutic targets for manipulating the antitumor immunity. In recent years, monoclonal antibodies or small molecule inhibitors targeting the CD39/CD73/A2AR pathway have been investigated in clinical trials as single agents or in combination with anti-PD-1/PD-L1 therapies. In this review, we provide an updated summary about the pathophysiological function of the adenosinergic pathway in cancer development, metastasis and drug resistance. The targeting of one or more components of the adenosinergic pathway for cancer therapy and circumvention of immunotherapy resistance are also discussed. Emerging biomarkers that may be used to guide the selection of CD39/CD73/A2AR-targeting treatment strategies for individual cancer patients is also deliberated.
    Keywords:  A2AR; Adenosine receptor; CD39; CD73; Cancer immunotherapy; Immunosuppressive tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-023-01733-x
  5. Mol Cancer Ther. 2023 Mar 02. 22(3): 291-305
    Interplay Between Extracellular Matrix Remodeling and Angiogenesis in Tumor Ecosystem.
    Rohit Siddhartha, Minal Garg.
      Studying the complex mechanisms of tumorigenesis and examining the interactions of neoplastic cells within tumor ecosystem are critical to explore the possibility of effective cancer treatment modalities. Dynamic tumor ecosystem is constantly evolving and is composed of tumor cells, extracellular matrix (ECM), secreted factors, and stromal cancer-associated fibroblasts (CAF), pericytes, endothelial cells (EC), adipocytes, and immune cells. ECM remodeling by synthesis, contraction, and/or proteolytic degradation of ECM components and release of matrix-sequestered growth factors create a microenvironment that promotes EC proliferation, migration, and angiogenesis. Stromal CAFs release multiple angiogenic cues (angiogenic growth factors, cytokines, and proteolytic enzymes) which interact with ECM proteins, thus contribute to enhance proangiogenic/promigratory properties and support aggressive tumor growth. Targeting angiogenesis brings about vascular changes including reduced adherence junction proteins, basement membrane and pericyte coverage, and increased leakiness. This facilitates ECM remodeling, metastatic colonization and chemoresistance. Owing to significant role of denser and stiffer ECM in inducing chemoresistance, direct or indirect targeting of ECM components is being reported as major axis of anticancer treatment. Exploring the agents targeting angiogenesis and ECM in a context specific manner may lead to reduced tumor burden by promoting conventional therapeutic effectiveness and overcoming the hurdles of therapy resistance.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-22-0595
  6. APMIS. 2023 Mar 03.
    Multiple myeloma cell-derived exosomes promote tumor favorable functional performance by polarization of macrophages toward M2 like cells.
    Bahman Razi, Masoud Soleimani, Mina Soufi-Zomorrod, Ahmad Adeli, Noushin Davoudi.
      It has long been hypothesized that leukemic cells are able to modulate the fate of resident cells in tumoral microenvironment toward a supporting and immunosuppressive cell for development of tumor. Exosome can be a potential culprit in imposing tumor desire. There are evidences about impact of tumor-derived exosome on different immune cells in different malignancies. However, findings about macrophages are contradictory. Here, we evaluated the potential influence of Multiple myeloma (MM)-cell derived exosome on polarization of macrophages by examining hallmarks for M1 and M2 macrophages. After treatment of M0 macrophages with isolated exosomes (from U266B1), gene expression (Arg-1, IL-10, TNF-α and IL-6), immunophenotyping markers (CD206), cytokine secretion (IL-10 and IL-6), nitric oxide (NO) production, and redox potentiality of target cell were assessed. Our results revealed significantly increased expression of the genes involved in development of M2 like cells but not M1 cells. CD 206 marker and IL-10 protein level (specific for M2 like cells) were significantly increased in different time points. The expression of IL-6 mRNA and IL-6 protein secretion did not change significantly. MM-cell derived exosomes induced significant changes in the NO production and intracellular ROS levels in M0 cells.
    Keywords:  Exosome; Macrophage polarization; Multiple myeloma
    DOI:  https://doi.org/10.1111/apm.13306
  7. Cell Metab. 2023 Feb 23. pii: S1550-4131(23)00042-6. [Epub ahead of print]
    Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity.
    Mualla Ozcan, Zhen Guo, Carla Valenzuela Ripoll, Ahmed Diab, Antonino Picataggi, David Rawnsley, Aynaz Lotfinaghsh, Carmen Bergom, Jeff Szymanski, Daniel Hwang, Aarti Asnani, Mikhail Kosiborod, Jie Zheng, Robert J Hayashi, Pamela K Woodard, Attila Kovacs, Kenneth B Margulies, Joel Schilling, Babak Razani, Abhinav Diwan, Ali Javaheri.
      Fasting strategies are under active clinical investigation in patients receiving chemotherapy. Prior murine studies suggest that alternate-day fasting may attenuate doxorubicin cardiotoxicity and stimulate nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. In this study, human heart tissue from patients with doxorubicin-induced heart failure demonstrated increased nuclear TFEB protein. In mice treated with doxorubicin, alternate-day fasting or viral TFEB transduction increased mortality and impaired cardiac function. Mice randomized to alternate-day fasting plus doxorubicin exhibited increased TFEB nuclear translocation in the myocardium. When combined with doxorubicin, cardiomyocyte-specific TFEB overexpression provoked cardiac remodeling, while systemic TFEB overexpression increased growth differentiation factor 15 (GDF15) and caused heart failure and death. Cardiomyocyte TFEB knockout attenuated doxorubicin cardiotoxicity, while recombinant GDF15 was sufficient to cause cardiac atrophy. Our studies identify that both sustained alternate-day fasting and a TFEB/GDF15 pathway exacerbate doxorubicin cardiotoxicity.
    Keywords:  TFEB; cardiotoxicity; doxorubicin; intermittent fasting
    DOI:  https://doi.org/10.1016/j.cmet.2023.02.006
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