A paracrine activin A-mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming.

EMBO Molecular Medicine
Michael CangkramaSabine Werner

Abstract

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.

References

Nov 1, 1973·Journal of the National Cancer Institute·D J GiardW P Parks
May 4, 2002·Nature Reviews. Molecular Cell Biology·James J TomasekRobert A Brown
May 16, 2003·Molecular and Cellular Biology·T Guy HamiltonPhilippe Soriano
Jan 26, 2005·Current Biology : CB·Stéphanie Pellegrin, Harry Mellor
Mar 1, 2005·Cancer Research·Inke Diana SchaperHerbert Pfister
Mar 17, 2005·Journal of Cell Science·Sophie ClémentChristine Chaponnier
Feb 17, 2006·Cytokine & Growth Factor Reviews·Sabine Werner, Christian Alzheimer
Feb 5, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Hirokazu OginoSaburo Sone
Feb 22, 2008·The EMBO Journal·Tomasz WilanowskiStephen M Jane
May 8, 2008·Proceedings of the National Academy of Sciences of the United States of America·R Scott PearsallMary L Bouxsein
Jun 3, 2008·Nature Cell Biology·Petra BeliMetello Innocenti
Jul 17, 2008·Nature Reviews. Molecular Cell Biology·Matthias Schäfer, Sabine Werner
Dec 23, 2009·Archives of Dermatology·W Elliot LoveJeremy S Bordeaux
Apr 9, 2011·Proceedings of the National Academy of Sciences of the United States of America·Roya NavabMing-Sound Tsao
May 28, 2011·Experimental Dermatology·Suzan CommandeurAbdoelwaheb El Ghalbzouri
Dec 14, 2011·Molecular & Cellular Proteomics : MCP·Alexandra NabaRichard O Hynes
Jan 19, 2012·The British Journal of Dermatology·A LomasF Bath-Hextall
Sep 20, 2012·Journal of Cell Science·Maria Antsiferova, Sabine Werner
Oct 2, 2012·Molecular Cancer Research : MCR·George S KaragiannisEleftherios P Diamandis
Nov 30, 2012·Nucleic Acids Research·Tanya BarrettAlexandra Soboleva
Dec 12, 2012·Breast Cancer Research : BCR·Colleen A FordyceThea D Tlsty
Jun 19, 2013·Trends in Molecular Medicine·Shalom MadarVarda Rotter
Jun 19, 2013·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Laurent SulpiceCédric Coulouarn
Nov 15, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Maria AntsiferovaSabine Werner
Jan 15, 2014·Seminars in Cancer Biology·A CalonE Batlle
Apr 3, 2014·The Journal of Clinical Investigation·G Paolo Dotto
Aug 2, 2014·The Journal of Investigative Dermatology·Magdalena HeinzPeter Petzelbauer
Feb 16, 2015·Molecular & Cellular Proteomics : MCP·Tadamoto IsogaiMetello Innocenti

❮ Previous
Next ❯

Citations

Mar 28, 2020·EMBO Molecular Medicine·Remi Samain, Victoria Sanz-Moreno
Feb 9, 2021·Frontiers in Cell and Developmental Biology·Jenniffer LinaresAlexandre Calon
Jan 15, 2021·Journal of Cell Science·Sarah T BoyleMichael S Samuel
Apr 4, 2021·Cancers·Rushikesh S JoshiManish K Aghi
May 1, 2021·International Journal of Molecular Sciences·Lucio Díaz-FloresPablo Martín-Vasallo
Jul 14, 2021·Nature Chemical Biology·Matthew R AronoffHelma Wennemers
Aug 7, 2021·Biomedicines·Wanglong QiuGloria H Su

❮ Previous
Next ❯

Datasets Mentioned

BETA
GSE45001
GSE9014
GSE35602

Methods Mentioned

BETA
xenograft
nuclear translocation
transgenic
FACS
flow cytometry
immunoprecipitation
Transfection
electrophoresis
ChIP
PCR

Software Mentioned

FastQC
GSEA
ImageJ
GEO2R
GraphPad
KMPlotter
Prism

Related Concepts

Related Feeds

Cancer Metabolic Reprogramming

Cancer metabolic reprogramming is important for the rapid growth and proliferation of cancer cells. Cancer cells have the ability to change their metabolic demands depending on their environment, regulated by the activation of oncogenes or loss of tumor suppressor genes. Here is the latest research on cancer metabolic reprogramming.

Cancer Metabolic Reprogramming (Keystone)

Cancer metabolic reprogramming is important for the rapid growth and proliferation of cancer cells. Cancer cells have the ability to change their metabolic demands depending on their environment, regulated by the activation of oncogenes or loss of tumor suppressor genes. Here is the latest research on cancer metabolic reprogramming.

Cell Migration in Cancer and Metastasis

Migration of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. Discover the latest research on cell migration in cancer and metastasis here.

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.