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      A framework for advancing our understanding of cancer-associated fibroblasts

      review-article

      , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 5 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 5 , 15 , 16 , 17 , 18 , 5 , 19 , 32 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 5 , 28 , 29 , 30 , 31

      Nature Reviews. Cancer

      Nature Publishing Group UK

      Cancer microenvironment, Metastasis, Extracellular matrix, Cancer therapy, Cancer therapeutic resistance

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          Abstract

          Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.

          Abstract

          This Consensus Statement highlights the importance of cancer-associated fibroblasts in cancer biology and progression, and issues a call to action for all cancer researchers to standardize assays and report metadata in studies of cancer-associated fibroblasts to advance our understanding of this important cell type in the tumour microenvironment.

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          Most cited references 102

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          Tensional homeostasis and the malignant phenotype.

          Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
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            Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.

            A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-β pathway, yet, paradoxically, they are characterized by elevated TGF-β production. Here, we unveil a prometastatic program induced by TGF-β in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-β on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-β-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-β stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Distinct fibroblast lineages determine dermal architecture in skin development and repair

              Fibroblasts are the major mesenchymal cell type in connective tissue and deposit the collagen and elastic fibers of the extracellular matrix (ECM) 1 . Even within a single tissue fibroblasts exhibit remarkable functional diversity, but it is not known whether this reflects the existence of a differentiation hierarchy or is a response to different environmental factors. Here we show, using transplantation assays and lineage tracing, that the fibroblasts of skin connective tissue arise from two distinct lineages. One forms the upper dermis, including the dermal papilla that regulates hair growth and the arrector pili muscle (APM), which controls piloerection. The other forms the lower dermis, including the reticular fibroblasts that synthesise the bulk of the fibrillar ECM, and the pre-adipocytes and adipocytes of the hypodermis. The upper lineage is required for hair follicle formation. In wounded adult skin, the initial wave of dermal repair is mediated by the lower lineage and upper dermal fibroblasts are recruited only during re-epithelialisation. Epidermal beta-catenin activation stimulates expansion of the upper dermal lineage, rendering wounds permissive for hair follicle formation. Our findings explain why wounding is linked to formation of ECM-rich scar tissue that lacks hair follicles 2-4 . They also form a platform for discovering fibroblast lineages in other tissues and for examining fibroblast changes in ageing and disease.
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                Author and article information

                Contributors
                erik.sahai@crick.ac.uk
                Journal
                Nat Rev Cancer
                Nat. Rev. Cancer
                Nature Reviews. Cancer
                Nature Publishing Group UK (London )
                1474-175X
                1474-1768
                24 January 2020
                24 January 2020
                2020
                : 20
                : 3
                : 174-186
                Affiliations
                [1 ]ISNI 0000 0004 1795 1830, GRID grid.451388.3, The Francis Crick Institute, ; London, UK
                [2 ]ISNI 0000 0004 0456 6466, GRID grid.412530.1, Marvin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, ; Philadelphia, PA USA
                [3 ]ISNI 0000 0004 0456 6466, GRID grid.412530.1, Cancer Biology Program, , Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, ; Philadelphia, PA USA
                [4 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Division of Oncology, , Washington University Medical School, ; St Louis, MO USA
                [5 ]ISNI 0000 0004 0387 3667, GRID grid.225279.9, Cold Spring Harbor Laboratory, ; Cold Spring Harbor, NY USA
                [6 ]ISNI 0000 0001 0662 7144, GRID grid.250671.7, Gene Expression Laboratory, Salk Institute for Biological Studies, ; La Jolla, CA USA
                [7 ]ISNI 0000 0001 0662 7144, GRID grid.250671.7, Howard Hughes Medical Institute, Salk Institute for Biological Studies, ; La Jolla, CA USA
                [8 ]ISNI 000000041936877X, GRID grid.5386.8, Weill Cornell Medicine, ; New York, NY USA
                [9 ]ISNI 0000 0001 1088 7029, GRID grid.418483.2, Institute for Tumor Biology and Experimental Therapy, , Georg-Speyer-Haus, ; Frankfurt, Germany
                [10 ]ISNI 0000 0004 1936 9721, GRID grid.7839.5, Frankfurt Cancer Institute, Goethe University Frankfurt, ; Frankfurt, Germany
                [11 ]ISNI 0000 0001 2180 1622, GRID grid.270240.3, Fred Hutchinson Cancer Research Center, ; Seattle, WA USA
                [12 ]ISNI 0000 0001 0662 7144, GRID grid.250671.7, Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, ; La Jolla, CA USA
                [13 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, ; Cambridge, MA USA
                [14 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Edwin L Steele Laboratories, Department of Radiation Oncology, , Massachusetts General Hospital, Harvard Medical School, ; Boston, MA USA
                [15 ]ISNI 0000 0001 2168 3646, GRID grid.416477.7, Northwell Health Cancer Institute, ; New Hyde Park, NY USA
                [16 ]ISNI 0000000121662407, GRID grid.5379.8, Cancer Research UK Manchester Institute, University of Manchester, ; Nether Alderley, UK
                [17 ]ISNI 0000 0001 2109 4251, GRID grid.240324.3, Department of Radiation Oncology, Perlmutter Cancer Center, , New York University Medical Center, ; New York, NY USA
                [18 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Sciences Center at Houston, ; Houston, TX USA
                [19 ]ISNI 0000 0001 2168 3646, GRID grid.416477.7, Northwell Health Cancer Institute, ; New York, NY USA
                [20 ]ISNI 0000 0001 2216 9681, GRID grid.36425.36, Department of Pathology, , Stony Brook University, ; Stony Brook, NY USA
                [21 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Biomedical Sciences, , School of Veterinary Medicine, University of Pennsylvania, ; Philadelphia, PA USA
                [22 ]Zucker School of Medicine at Hofstra/Northwell Health System, New York, NY USA
                [23 ]ISNI 0000 0004 0604 7563, GRID grid.13992.30, Department of Biomolecular Sciences, , The Weizmann Institute of Science, ; Rehovot, Israel
                [24 ]ISNI 0000 0000 9758 5690, GRID grid.5288.7, Department of Cell, Developmental & Cancer Biology, , Oregon Health & Science University, ; Portland, OR USA
                [25 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Department of Cell Biology and Physiology, Department of Medicine, , ICCE Institute, Siteman Cancer Center, Washington University School of Medicine, ; St Louis, MO USA
                [26 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, UCSF Helen Diller Comprehensive Cancer Center, ; San Francisco, CA USA
                [27 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Pathology, , UCSF, ; San Francisco, CA USA
                [28 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Centre for Stem Cells and Regenerative Medicine, , King’s College London, Guy’s Hospital, ; London, UK
                [29 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Center for Bioengineering and Tissue Regeneration, Department of Surgery, , University of California, San Francisco, ; San Francisco, CA USA
                [30 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, ; Baltimore, MD USA
                [31 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Anatomy, , University of California, San Francisco, ; San Francisco, CA USA
                [32 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Present Address: Abramson Cancer Center, University of Pennsylvania, ; Philadelphia, PA USA
                Article
                238
                10.1038/s41568-019-0238-1
                7046529
                31980749
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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                © Springer Nature Limited 2020

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