VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS |
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The VIMM, established in 2008 by Paul B. Fisher, MPh, PhD, FNAI, the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine and external affiliate members focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by VIMM members.
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Hypoxia Helps Cancer Cheat in Cell Competition |
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The study from Dr. Gogna (VIMM) and colleagues, including Drs. Sarmistha Talukdar and Paul B. Fisher (VIMM), has unraveled the connection between hypoxia-inducible factor-mediated transcriptional changes and dysregulation of cell competition (CC) pathways, which promote tumorigenesis and metastasis.
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Various pathways are involved in CC, which tumor cells rely on to acquire a competitive advantage leading to growth and metastasis.
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Hypoxia is characterized by low oxygen levels; CC and hypoxia have been associated, as the expression of some CC related genes is influenced by hypoxia inducible factors and influences cancer outcome.
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Clonal stem cell selection contributes to tumor heterogeneity because the development of mutations in a fraction of stem cells in a niche can lead to their selection. This heterogeneity contributes to competition, which ultimately affects cancer detection, targeting, and prognosis. (Contribution of Drs. Talukdar and Fisher, VIMM)
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CC maintains immune homeostasis, function, and development, which prevents immune malignancies.
Cell competition (CC) underlies many tissue processes, such as tissue development, growth, regeneration and suppression/growth of cancer (1, 2). Comparison of fitness fingerprints between cells allows the most fit cells, so called winners, to outcompete and eliminate less fit cells, losers, ensuring optimal tissue composition and function. Cells compete for nutrients, growth factors or space, and successful acquisition of valuable resources promotes the expansion of winners. While CC functions to inhibit carcinogenesis (3), cancers find ways to “cheat” and subvert these pathways to promote their growth and win against all odds. As reviewed by *Madan et. al., several competitive processes regulate tumor initiation and progression including selective expression of winner-fitness fingerprints, hypoxia, clonal selection and immune dysregulation (4).
Cancers utilize a disproportionate amount of nutrients and oxygen to promote their growth, leading to a relatively resource poor and hypoxic tumor microenvironment (TME). Cells respond to hypoxia by affecting gene expression through hypoxia-inducible factors (HIFs), which alter metabolism, proliferation, function and survival of cells within the TME. Madan and colleagues have unraveled the connection between HIF-mediated transcriptional changes and dysregulation of CC pathways, which promote tumorigenesis and metastasis. Specifically, they found hypoxia upregulate many genes involved in CC and highlighted recent evidence that shows how hypoxia can select for apoptosis-resistant cells, highlighting a fundamental connection between hypoxia and CC (4).
They also discovered that when CC between stem cells goes awry, incipient cancers gain a competitive advantage and produce a clonal population of cells that outcompete healthy neighbors in tissue niches, which ultimately selects for cancer stem cells (CSCs). As the CSC populations continue to expand, they can acquire new mutations, which endow them with new capabilities such as chemo-/radio-resistance. Subsequent anti-cancer treatment could then further select for this malignant population. The information presented in this review* highlights how CC elucidates the complementarity of the clonal evolution and CSC models of carcinogenesis. (Contribution of Drs. Talukdar and Fisher, VIMM)
Tumor immunology and dysregulation of the immune system during carcinogenesis has become a booming area of research. A dysfunctional immune system predisposes individuals to cancer, yet few studies have elucidated the CC pathways involved. Furthermore, hypoxia and nutrient depletion in the TME induce immunosuppressive metabolic and epigenetic alterations in immune cells (6). Madan et. al. take the reader from the bone marrow to the TME and highlight the complexity of CC in mediating the interaction between immune cells, and between immune cells and cancers as the immune system attempts to prevent carcinogenesis (4). Many of the insights presented in this review will undoubtedly change the way we approach the biology and treatment of cancer.
This work was supported by Champalimaud Foundation research funds, Portugal, ERC European funding, and La Caixa, Spain (LCF/BQ/PR20/11770006). In addition, it acknowledges research support from NIH R01 CA244993 and the National Foundation for Cancer Research (NFCR), NIH R01 CA194013 and NIH R01 CA192064, NIH R01AR063611, NIH R01AI119041, and NIH R01AR069681.
Publications:
2. Parker T, Madan E, Gupta K, Moreno E, Gogna R. Cell Competition Spurs Selection of Aggressive Cancer Cells. Trends Cancer. 2020 Sep;6(9):732-736. DOI: 10.1016/j.trecan.2020.03.008
4. *Madan E, Peixoto ML, Dimitrion P, Eubank TD, Yekelchyk M, Talukdar S, Fisher PB, Mi QS, Moreno E, Gogna R. Cell Competition Boosts Clonal Evolution and Hypoxic Selection in Cancer. Trends Cell Biol. 2020 Dec;30(12):967-978. DOI: 10.1016/j.tcb.2020.10.002
5. Madan E, Pelham CJ, Nagane M, Parker TM, Canas-Marques R, Fazio K, Shaik K, Yuan Y, Henriques V, Galzerano A, Yamashita T, Pinto MAF, Palma AM, Camacho D, Vieira A, Soldini D, Nakshatri H, Post SR, Rhiner C, Yamashita H, Accardi D, Hansen LA, Carvalho C, Beltran AL, Kuppusamy P, Gogna R, Moreno E. Flower isoforms promote competitive growth in cancer. Nature. 2019 Aug;572(7768):260-264. DOI: 10.1038/s41586-019-1429-3
6. Ivashkiv LB. The hypoxia-lactate axis tempers inflammation. Nat Rev Immunol 2020 Feb;20(2):85-86. PMCID: PMC7021227
About the Investigators: Esha Madan, Maria Leonor Peixoto, Eduardo Moreno and and Rajan Gogna are from Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal. Rajan Gogna holds an affiliate faculty position in the Department of Human and Molecular Genetics, and VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA. Peter Dimitrion is affiliated with Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, MI, USA, Immunology Research Program Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI, USA and Department of Biochemistry, Microbiology and Immunology, Wayne State University Medical School, Detroit, MI, USA. Timothy D. Eubank is affiliated with the In Vivo Multifunctional Magnetic Resonance Center, Robert C. Byrd Health Sciences Center, and Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV, USA. Michail Yekelchyk is affiliated with the Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany. Sarmistha Talukdar is a Postdoctoral Research Scientist and Paul B. Fisher is Professor and Chair, Department of Human and Molecular Genetics, Director of the VCU Institute of Molecular Medicine, and Thelma Newmeyer Corman Chair in Oncology, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
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Relevant Figures from the Review (Maden et al., Trends Cell Biology, 2020): |
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Figure 1. Cell Competition-Dependent Mechanisms That Promote Cancer Aggressiveness. Note: Click image to expand in separate window. (A) Representation of a tumor region where tumor cell proliferation and/or vessel dysfunction has created a site of hypoxia distal from accessible oxygen diffusion. Other tumor regions remain with normal oxygen levels (normoxia). Hypoxia activates pathways in some hypoxic cells that generate a fitness winner phenotype, while neighboring cells in the hypoxic region display a fitness loser phenotype and undergo apoptosis. (B) Cell competition selects for hypoxic cells and MUT p53 cells. Under hypoxic conditions, p53 complexes with hypoxia inducible factor 1 alpha (HIF-1α) and acquires a mutant-like conformation independent of its genetic sequence. Hypoxic cells and cells harboring a p53 mutation (MUT p53) outcompete their normoxic wild-type (WT) counterparts, leading to neoplastic growth. (C) Human high-grade serous ovarian carcinoma sample stained with hematoxylin and eosin (H&E) (left) and with anti-HIF-1α (right). The image shows hypoxic tumor regions with predominant HIF-1α stabilization (nuclear staining; orange arrowheads) and normoxic tumor regions (blue arrowheads). Hypoxia has been reported to trigger cell fitness pathways including MYC, WNT, DPP, JAK, Hippo, and Scribble and their downstream effectors JNK, p53, Azot, NF-kB, and Sparc.
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Figure 2. Examples of Cell Competition (CC) in Cancer Stem Cell (CSC) Selection and Immune Cell Development. Note: Click image to expand in separate window. (A) Hypothetical schematic diagram illustrating the evolution of CSCs encountering competitive environments. The cells with red nuclei are depicted here as non-stem cancer cells and the cells without the red nuclei are depicted as CSCs. The light blue cells in this diagram represent the original CSCs, which divide to give rise to daughter CSCs (light blue) and non-stem cancer cells (light blue with red nuclei). Over time, the CSCs acquire mutations (and/or epigenetic changes). The CSCs with the 1st mutation (epigenetic change) are the dark-blue cells; the CSCs with the 2nd, 3rd, 4th, and 5th mutations (and/or epigenetic changes, or a combination of both changes) are the light-purple, dark purple, black, and red cells, respectively. Consequently, over time, multiple mutant CSCs can exist in any give tumor. These CSCs compete with each other for resources. Under stressful conditions such as chemotherapy or irradiation, the competition among the CSCs becomes more intense and only a few CSCs can win because of mutations (and/or epigenetic changes) that give them a selective advantage under stressful situations. During the evolution of the tumor, the light-purple and the dark-purple CSCs survive chemotherapy; however, only the black CSCs survive radiation. These CSCs can acquire another mutations (epigenetic changes) (red CSC). In this way, the multiple competing CSCs evolve over time and accumulate additional mutations (and/or epigenetic changes) that provide a survival advantage over other CSCs. This is a continuous process of clonal evolution that is amplified by selective pressures (hypoxia, chemotherapy, irradiation, nutrient deprivation). (B) In the bone marrow, p53 mediates CC. Cells with lower p53 induce senescence of cells with higher p53. How hematopoietic stem cells (HSCs) communicate and compare their levels of p53 remains unknown, but studies highlighting the inhibitory role of Ca2+ provide a solution. WT, wild type. (C) In the thymus, thymocytes compete for interleukin-1 (IL-7), analogous to competition for Dpp in fly imaginal discs. Normally, long dwell times in the thymus reduce the efficiency with which older thymocytes can utilize IL-7 and are replaced by younger thymocytes. However, when younger thymocyte (blue) cannot utilize IL-7 due to a genetic deficiency, they are outcompeted by older thymocytes, and long dwell times in older thymocytes lead to genetic insult, which progresses to a T cell acute lymphoblastic leukemia (T-ALL)-like phenotype. (D) Cancer cells can utilize most of the metabolic substrates in the tumor microenvironment (TME). Thus, the TME is a nutrient-deprived, lactate-rich environment. This promotes the differentiation of immunosuppressive myeloid and lymphoid cells, which subsequently drives carcinogenesis. (E) Lymphocytes must come into physical contact with dendritic cells to become activated. The mechanism for this competition is not known, nor is the outcome of less-fit lymphocytes.
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