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SCD5-dependent inhibition of SPARC secretion hampers metastatic spreading and favors host immunity in a TNBC murine model

Oncogene volume 41, pages 4055–4065 (2022)Cite this article

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Abstract

Dysregulated fatty acid metabolism interacts with oncogenic signals, thereby worsening tumor aggressiveness. The stearoyl-CoA desaturating enzymes, SCD1 and SCD5, convert of saturated fatty acids to monounsaturated fatty acids. While SCD1 is frequently overexpressed in tumor cells and has been widely studied, SCD5 has both limited expression and poor characterization. Here we evaluated, in vitro and in vivo, the effects of SCD5 overexpression in a metastatic clone of 4T1. The results showed SCD5-driven reprogramming of fatty acid metabolism, involving desaturation of stearic acid to oleic acid, which eventually blocked SPARC secretion. The latter event reduced the aggressiveness of the 4T1 subclone by decreasing the ECM deposition and reverting the Epithelial to Mesenchymal Transition (EMT) status. Variation of the fatty acid profile by SCD5-gene transduction or the direct administration oleic acid reduces the immune suppressive activity of myeloid cells and promoting granulocytic myeloid-derived suppressor cell maturation, eventually favoring T-cell activation. The less immunosuppressive microenvironment generated by SCD5 overexpression was enhanced in Sparc-KO mice, indicating that both extracellular and endogenous SPARC additively regulate myeloid cell-suppressive activities. Overall, our data sheds light on exploring the oleic acid-dependent inhibition of SPARC secretion as a possible mechanism to reduce breast cancer malignancy.

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Fig. 1: Functional characterization of 4T1cl5 triple-negative murine cell line.
Fig. 2: SCD5 overexpression in 4T1cl5 cells blocks SPARC extracellular secretion through oleic acid.
Fig. 3: SCD5 reduces breast cancer malignancy in vivo by extracellular matrix remodeling.
Fig. 4: MDSC hematopoietic and CD8+ T-lymphocyte subpopulations are affected by SCD5 expression in metastasized lung.
Fig. 5: SCD5-related downregulation of Arginase1 and Fatty Acid Oxidation (FAO) key enzymes.
Fig. 6: SCD5 potentiates the reduction of the malignant phenotype in Sparc-Ko mice.
Fig. 7: SCD5 associated changes of chemokine and cytokine levels in wild-type and Sparc-KO mice.

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Acknowledgements

This work was supported by AIRC IG n°. 22204 to SS, IG n°. 24363 to MPC and IG n° 18815 to AC. MB was partially supported by the FIRC-AIRC fellowship “Fabrizio Ansuini” n. 22474, GT was supported by the FIRC-AIRC fellowship “Giorgio Boglio’ n°. 22460, and CT by Fondazione Umberto Veronesi, which we gratefully acknowledge.

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Authors and Affiliations

  1. Center for Gender-Specific Medicine, Istituto Superiore di Sanità, Rome, Italy

    Maria Bellenghi, Rossella Puglisi, Giada Pontecorvi, Alessandra Carè & Gianfranco Mattia

  2. Molecular Immunology Unit, Department of Research, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy

    Giovanna Talarico, Laura Botti, Paola Portararo, Annamaria Piva, Mario P. Colombo & Sabina Sangaletti

  3. Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy

    Claudio Tabolacci

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Contributions

SS designed the study; MB, RP, GT, GP, LB, PP, and SS performed the experiments and analyzed the data; CT performed cytokine and interleukin multiplex analysis; AP performed in silico analysis of TNBC patients; MB, GM, and SS wrote the manuscript; MPC and AC participated in study coordination and critically reviewed the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Gianfranco Mattia or Sabina Sangaletti.

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Supplementary information

Supplemental Methods and Suppl Figure Legends

Supplementary Table 1

Supplementary Figure 1 Evaluation of the SCD1 (SCD) and SCD5 expressions in public available datasets of TNBC.

Supplementary Figure 2. SCD5 overexpression in 4T1cl5 cell line.

Supplementary Figure 3. Intracellular retention of collagen IV/SPARC complexes in 4T1cl5/SCD5 cells.

Supplementary Figure 4. SCD5 enforced expression and oleic acid induce epithelial morphology in 4T1cl5 cells.

Supplementary Figure 5. Evaluation of granzyme B of tumor-associated CD8 T-cells

Supplementary Figure 6. Treg characterization in lung and tumor of either WT and Sparc-KO mice

Supplementary Figure 7. SCD5 potentiates fatty acid reprogramming of MDSCs in Sparc-deficient host.

Supplementary Figure 8. SCD5 systemic events in shaping immune response phenotype.

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Bellenghi, M., Talarico, G., Botti, L. et al. SCD5-dependent inhibition of SPARC secretion hampers metastatic spreading and favors host immunity in a TNBC murine model. Oncogene 41, 4055–4065 (2022). https://doi.org/10.1038/s41388-022-02401-y

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