A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming

Cancer‐associated fibroblasts (CAFs) are key regulators of tumorigenesis and promising targets for next‐generation therapies. We discovered that cancer cell‐derived activin A reprograms fibroblasts into pro‐tumorigenic CAFs. Mechanistically, this occurs via Smad2‐mediated transcriptional regulation of the formin mDia2, which directly promotes filopodia formation and cell migration. mDia2 also induces expression of CAF marker genes through prevention of p53 nuclear accumulation, resulting in the production of a pro‐tumorigenic matrisome and secretome. The translational relevance of this finding is reflected by activin A overexpression in tumor cells and of mDia2 in the stroma of skin cancer and other malignancies and the correlation of high activin A/mDia2 levels with poor patient survival. Blockade of this signaling axis using inhibitors of activin, activin receptors, or mDia2 suppressed cancer cell malignancy and squamous carcinogenesis in 3D organotypic cultures, ex vivo, and in vivo, providing a rationale for pharmacological inhibition of activin A‐mDia2 signaling in stratified cancer patients.

[1]  S. Werner,et al.  Activin-mediated alterations of the fibroblast transcriptome and matrisome control the biomechanical properties of skin wounds , 2020, Nature Communications.

[2]  V. Sanz-Moreno,et al.  Cancer‐associated fibroblasts: activin A adds another string to their bow , 2020, EMBO molecular medicine.

[3]  R. Gutzmer,et al.  Hedgehog Pathway Inhibition for the Treatment of Basal Cell Carcinoma , 2019, Targeted Oncology.

[4]  Laura F. Dagley,et al.  Therapeutic blockade of activin-A improves NK cell function and antitumor immunity , 2019, Science Signaling.

[5]  Jordan F Hastings,et al.  Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy , 2018, Science Translational Medicine.

[6]  S. Werner,et al.  Nrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome. , 2018, Developmental cell.

[7]  A. Lánczky,et al.  Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets , 2018, Scientific Reports.

[8]  A. Hauschild,et al.  PD‐1 Blockade with Cemiplimab in Advanced Cutaneous Squamous‐Cell Carcinoma , 2018, The New England journal of medicine.

[9]  R. Weinberg,et al.  Understanding the tumor immune microenvironment (TIME) for effective therapy , 2018, Nature Medicine.

[10]  T. Graham,et al.  An evolutionary perspective on field cancerization , 2017, Nature Reviews Cancer.

[11]  D. Constam,et al.  Paracrine Activin-A signaling promotes melanoma growth and metastasis through immune evasion , 2017, bioRxiv.

[12]  Prahlad T. Ram,et al.  Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens. , 2017, JCI insight.

[13]  F. Abdul-Karim,et al.  Follistatin is a metastasis suppressor in a mouse model of HER2-positive breast cancer , 2017, Breast Cancer Research.

[14]  S. Werner,et al.  Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages , 2016, EMBO molecular medicine.

[15]  R. A. van der Kammen,et al.  Quantitative Proteomics Illuminates a Functional Interaction between mDia2 and the Proteasome. , 2016, Journal of proteome research.

[16]  Alexander E. Kel,et al.  GTRD: a database of transcription factor binding sites identified by ChIP-seq experiments , 2016, Nucleic Acids Res..

[17]  R. Kalluri.  The biology and function of fibroblasts in cancer , 2016, Nature Reviews Cancer.

[18]  P. Gascard,et al.  Carcinoma-associated fibroblasts: orchestrating the composition of malignancy , 2016, Genes & development.

[19]  E. Puré,et al.  Can Targeting Stroma Pave the Way to Enhanced Antitumor Immunity and Immunotherapy of Solid Tumors? , 2016, Cancer Immunology Research.

[20]  S. Feldman,et al.  Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012. , 2015, JAMA dermatology.

[21]  E. Giannoni,et al.  Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation , 2015 .

[22]  Dong Eun Kim,et al.  Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation , 2015, Nature Cell Biology.

[23]  Manuel Berning,et al.  Three-Dimensional In Vitro Skin and Skin Cancer Models Based on Human Fibroblast-Derived Matrix. , 2015, Tissue engineering. Part C, Methods.

[24]  R. A. van der Kammen,et al.  SMIFH2 has effects on Formins and p53 that perturb the cell cytoskeleton , 2015, Scientific Reports.

[25]  A. Heck,et al.  Proteomic Analyses Uncover a New Function and Mode of Action for Mouse Homolog of Diaphanous 2 (mDia2)* , 2015, Molecular & Cellular Proteomics.

[26]  E. Batlle,et al.  TGF-beta in CAF-mediated tumor growth and metastasis. , 2014, Seminars in cancer biology.

[27]  G. Dotto.  Multifocal epithelial tumors and field cancerization: stroma as a primary determinant. , 2014, The Journal of clinical investigation.

[28]  K. Eisenmann,et al.  An mDia2/ROCK Signaling Axis Regulates Invasive Egress from Epithelial Ovarian Cancer Spheroids , 2014, PloS one.

[29]  S. Werner,et al.  Mast Cells Are Dispensable for Normal and Activin-Promoted Wound Healing and Skin Carcinogenesis , 2013, The Journal of Immunology.

[30]  K. Boudjema,et al.  Molecular profiling of stroma identifies osteopontin as an independent predictor of poor prognosis in intrahepatic cholangiocarcinoma , 2013, Hepatology.

[31]  Fiona M. Watt,et al.  Distinct fibroblast lineages determine dermal architecture in skin development and repair , 2013, Nature.

[32]  Jinsong Liu,et al.  TGF-β modulates ovarian cancer invasion by upregulating CAF-derived versican in the tumor microenvironment. , 2013, Cancer research.

[33]  Shalom Madar,et al.  'Cancer associated fibroblasts'--more than meets the eye. , 2013, Trends in molecular medicine.

[34]  M. Hedger,et al.  The activins and their binding protein, follistatin-Diagnostic and therapeutic targets in inflammatory disease and fibrosis. , 2013, Cytokine & growth factor reviews.

[35]  Robert P. Jenkins,et al.  Mechano-transduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer associated fibroblasts , 2013, Nature Cell Biology.

[36]  K. Horwitz,et al.  Genomic Signatures of Pregnancy-Associated Breast Cancer Epithelia and Stroma and their Regulation by Estrogens and Progesterone , 2013, Hormones and Cancer.

[37]  T. Tlsty,et al.  Cell-extrinsic consequences of epithelial stress: activation of protumorigenic tissue phenotypes , 2012, Breast Cancer Research.

[38]  Sean R. Davis,et al.  NCBI GEO: archive for functional genomics data sets—update , 2012, Nucleic Acids Res..

[39]  Eleftherios P. Diamandis,et al.  Cancer-Associated Fibroblasts Drive the Progression of Metastasis through both Paracrine and Mechanical Pressure on Cancer Tissue , 2012, Molecular Cancer Research.

[40]  Sabine Werner,et al.  The bright and the dark sides of activin in wound healing and cancer , 2012, Journal of Cell Science.

[41]  J. McGrath,et al.  Fibroblast-derived dermal matrix drives development of aggressive cutaneous squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa. , 2012, Cancer research.

[42]  J. Leonardi-Bee,et al.  A systematic review of worldwide incidence of nonmelanoma skin cancer , 2012, The British journal of dermatology.

[43]  Steven A. Carr,et al.  The Matrisome: In Silico Definition and In Vivo Characterization by Proteomics of Normal and Tumor Extracellular Matrices , 2011, Molecular & Cellular Proteomics.

[44]  S. Werner,et al.  Activin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response , 2011, Nature communications.

[45]  K. Matsumoto,et al.  Activin A inhibits vascular endothelial cell growth and suppresses tumour angiogenesis in gastric cancer , 2011, British Journal of Cancer.

[46]  F. D. de Gruijl,et al.  Functional characterization of cancer‐associated fibroblasts of human cutaneous squamous cell carcinoma , 2011, Experimental dermatology.

[47]  M. Delorenzi,et al.  Identification of Prognostic Molecular Features in the Reactive Stroma of Human Breast and Prostate Cancer , 2011, PloS one.

[48]  Nikolina Radulovich,et al.  Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer , 2011, Proceedings of the National Academy of Sciences.

[49]  Eva M. Schmelz,et al.  Changes in Gene Expression and Cellular Architecture in an Ovarian Cancer Progression Model , 2011, PloS one.

[50]  D. Lacey,et al.  Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival , 2010, Cell.

[51]  J. Bernhard,et al.  Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review. , 2009, Archives of dermatology.

[52]  A. Friedl,et al.  Heterogeneity of Gene Expression in Stromal Fibroblasts of Human Breast Carcinomas and Normal Breast , 2009, Oncogene.

[53]  M. Rubin,et al.  Oncosome formation in prostate cancer: association with a region of frequent chromosomal deletion in metastatic disease. , 2009, Cancer research.

[54]  Matthias Schäfer,et al.  Cancer as an overhealing wound: an old hypothesis revisited , 2008, Nature Reviews Molecular Cell Biology.

[55]  Petra Beli,et al.  WAVE and Arp2/3 jointly inhibit filopodium formation by entering into a complex with mDia2 , 2008, Nature Cell Biology.

[56]  M. Bouxsein,et al.  A soluble activin Type IIA receptor induces bone formation and improves skeletal integrity , 2008, Proceedings of the National Academy of Sciences.

[57]  John M Cunningham,et al.  Perturbed desmosomal cadherin expression in grainy head‐like 1‐null mice , 2008, The EMBO journal.

[58]  Kunihiro Tsuchida,et al.  Follistatin Suppresses the Production of Experimental Multiple-Organ Metastasis by Small Cell Lung Cancer Cells in Natural Killer Cell–Depleted SCID Mice , 2008, Clinical Cancer Research.

[59]  M. Oren,et al.  p53 Attenuates cancer cell migration and invasion through repression of SDF-1/CXCL12 expression in stromal fibroblasts. , 2006, Cancer research.

[60]  W. Sterry,et al.  Identification of differentially expressed genes in cutaneous squamous cell carcinoma by microarray expression profiling , 2006, Molecular Cancer.

[61]  Sabine Werner,et al.  Roles of activin in tissue repair, fibrosis, and inflammatory disease. , 2006, Cytokine & growth factor reviews.

[62]  H. Augustin,et al.  Dissociation of angiogenesis and tumorigenesis in follistatin- and activin-expressing tumors. , 2006, Cancer research.

[63]  B. Hinz,et al.  The N-terminal Ac-EEED sequence plays a role in α-smooth-muscle actin incorporation into stress fibers , 2005, Journal of Cell Science.

[64]  P. Fuchs,et al.  Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8. , 2005, Cancer research.

[65]  H. Mellor,et al.  The Rho Family GTPase Rif Induces Filopodia through mDia2 , 2005, Current Biology.

[66]  K. Kuchler,et al.  Activin A Signaling Induces Smad2, but Not Smad3, Requiring Protein Kinase A Activity in Granulosa Cells from the Avian Ovary* , 2003, Journal of Biological Chemistry.

[67]  Philippe Soriano,et al.  Evolutionary Divergence of Platelet-Derived Growth Factor Alpha Receptor Signaling Mechanisms , 2003, Molecular and Cellular Biology.

[68]  B. Hinz,et al.  Myofibroblasts and mechano-regulation of connective tissue remodelling , 2002, Nature Reviews Molecular Cell Biology.

[69]  R. Altman,et al.  Wild Type and Mutant p53 Differentially Regulate the Gene Expression of Human Collagenase-3 (hMMP-13)* , 2000, The Journal of Biological Chemistry.

[70]  R. Balling,et al.  Overexpression of activin A in the skin of transgenic mice reveals new activities of activin in epidermal morphogenesis, dermal fibrosis and wound repair , 1999, The EMBO journal.

[71]  M V Chernov,et al.  A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. , 1999, Science.

[72]  J. Rheinwald,et al.  Tumorigenic keratinocyte lines requiring anchorage and fibroblast support cultured from human squamous cell carcinomas. , 1981, Cancer research.

[73]  S. Aaronson,et al.  In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors. , 1973, Journal of the National Cancer Institute.

[74]  J. Bouwes Bavinck,et al.  Aggressive Squamous Cell Carcinoma in Organ Transplant Recipients , 2019, JAMA dermatology.

[75]  H. Pehamberger,et al.  Activin A is anti-lymphangiogenic in a melanoma mouse model. , 2015, The Journal of investigative dermatology.

[76]  M. Neeman,et al.  Molecular and Cellular Pathobiology P53 Status in Stromal Fibroblasts Modulates Tumor Growth in an Sdf1-dependent Manner , 2022 .

[77]  the original work is properly cited. , 2022 .