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STAT3 induces breast cancer growth via ANGPTL4, MMP13 and STC1 secretion by cancer associated fibroblasts

Oncogene volume 41, pages 1456–1467 (2022)Cite this article

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Abstract

In the tumor microenvironment, Cancer Associated Fibroblasts (CAFs) become activated by cancer cells and increase their secretory activity to produce soluble factors that contribute to tumor cells proliferation, invasion and dissemination to distant organs. The pro-tumorigenic transcription factor STAT3 and its canonical inducer, the pro-inflammatory cytokine IL-6, act conjunctly in a positive feedback loop that maintains high levels of IL-6 secretion and STAT3 activation in both tumor and stromal cells. Here, we demonstrate that STAT3 is essential for the pro-tumorigenic functions of murine breast cancer CAFs both in vitro and in vivo, and identify a STAT3 signature significantly enriched for genes encoding for secreted proteins. Among these, ANGPTL4, MMP13 and STC-1 were functionally validated as STAT3-dependent mediators of CAF pro-tumorigenic functions by different approaches. Both in vitro and in vivo CAFs activities were moreover impaired by MMP13 inhibition, supporting the feasibility of a therapeutic approach based on inhibiting STAT3-induced CAF-secreted proteins. The clinical potential of such an approach is supported by the observation that an equivalent CAF-STAT3 signature in humans is expressed at high levels in breast cancer stromal cells and characterizes patients with a shorter disease specific survival, including those with basal-like disease.

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Fig. 1: STAT3 is required for CAFs pro-tumorigenic functions.
Fig. 2: Immortalized CAFs show STAT3 dependent pro-tumorigenic features both in vitro and in vivo.
Fig. 3: STAT3 regulates the expression of several CAF-secreted proteins.
Fig. 4: IL-6 blockade impairs CAFs ability to support in vivo growth of 4T1 cells.
Fig. 5: Angptl4, MMP13 and Stc1 mediate in vitro CAFs pro-tumorigenic functions.
Fig. 6: Stc1 and Mmp13 strongly contribute to CAF-induced 4T1 tumors growth and progression.
Fig. 7: The CAF STAT3 signature is conserved in human breast cancer stroma and correlates with poor survival.

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Acknowledgements

The authors wish to thank D. Taverna, C. Ambrogio, E. Calautti, M. Mazzone for critically reading the manuscript. This work was supported by the Italian Cancer Research Association (AIRC, IG16930 to V.P.; IG 20240 to S.O.); the Italian Ministry of University and Research (MIUR PRIN 2017 to V.P.); the Truus and Gerrit van Riemsdijk Foundation, Liechtenstein, donation to V.P.; Piedmont Region (Deflect). L. Avalle was supported by Fondazione Umberto Veronesi.

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Author notes

  1. Laura Raggi

    Present address: San Raffaele-Telethon Institute for Gene Therapy (SR-TIGET), Milan, Italy

  2. Emanuele Monteleone

    Present address: Università Vita-Salute San Raffaele, Milan, Italy

  3. Luisa Statello

    Present address: Center for Applied Medical Research, University of Navarra, Pio XII 55 Ave, 31008, Pamplona, Spain

  4. Chiara Guglielmi

    Present address: Section of Molecular Genetics, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy

  5. Danny Incarnato

    Present address: Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, 9747 AG, Groningen, the Netherlands

  6. These authors contributed equally: Lidia Avalle, Laura Raggi, Emanuele Monteleone, Aurora Savino.

Authors and Affiliations

  1. Department of Molecular Biotechnology and Health Science, University of Torino, Via Nizza 52, 10126, Torino, Italy

    Lidia Avalle, Laura Raggi, Emanuele Monteleone, Aurora Savino, Daniele Viavattene, Luisa Statello, Andrea Camperi, Simona Aversano Stabile, Vincenzo Salemme, Niccolò De Marzo, Francesca Marino, Chiara Guglielmi, Andrea Lobascio, Paola Defilippi & Valeria Poli

  2. BioAir SPA Scientific Department, Via Nizza, 52, 10126, Torino, Italy

    Cristina Zanini & Marco Forni

  3. Department of Life Sciences and Systems Biology, University of Torino, Via Nizza 52, 10126, Torino, Italy

    Danny Incarnato & Salvatore Oliviero

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Contributions

Conception, design and study supervision VP; bioinformatics data generation and analysis, EM, AS, NDM, DI, SO; in vitro experiments, AC, CG, FM, SAS, LR, DV, AL, DI; in vivo experiments, LA, AC, LR, DV, SAS, VS; Acquisition of data, CZ and MF; Analysis and interpretation of data, EM, LA, AS, LR, DV, DI, VP, PD, SO.

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Correspondence to Lidia Avalle or Valeria Poli.

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Avalle, L., Raggi, L., Monteleone, E. et al. STAT3 induces breast cancer growth via ANGPTL4, MMP13 and STC1 secretion by cancer associated fibroblasts. Oncogene 41, 1456–1467 (2022). https://doi.org/10.1038/s41388-021-02172-y

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