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SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment.

ABSTRACT: Most tumors initially respond to cytotoxic treatments, but acquired resistance often follows. The tumor microenvironment (TME) is a major barrier to clinical success by compromising therapeutic efficacy, and pathological relevance of multiple soluble factors released by a therapeutically remodeled TME remains largely unexplored. Here we show that the secreted frizzled-related protein 2 (SFRP2), a Wnt pathway modulator, is produced by human primary fibroblasts after genotoxic treatments. SFRP2 induction is remarkable in tumor stroma, with transcription mainly modulated by the nuclear factor-?B (NF-?B) complex, a property shared by several effectors of the DNA damage secretory program. Instead of directly altering canonical Wnt signaling, SFRP2 augments ?-catenin activities initiated by WNT16B, another soluble factor from DNA-damaged stroma. WNT16B recognizes cancer cell surface receptors including frizzled (FZD) 3/4/6, a process enhanced by SFRP2, coordinated by the co-receptor LRP6 but subject to abrogation by DKK1. Importantly, we found WNT16B plays a central role in promoting advanced malignancies particularly acquired resistance by counteracting cell death, an effect that can be minimized by a neutralizing antibody co-administered with classical chemotherapy. Furthermore, DNA damage-triggered expression of WNT16B is systemic, imaged by significant induction among diverse solid organs and circulation in peripheral blood, thereby holding promise as not only a TME-derived anticancer target but also a novel biomarker for clinical evaluation of treatment efficacy. Overall, our study substantiates the biological complexity and pathological implication of a therapy-activated TME, and provides the proof of principle of co-targeting tumor and the TME to prevent acquired resistance, with the aim of improving intervention outcome in an era of precision medicine.

SUBMITTER: Sun Y

PROVIDER: S-EPMC4994019 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment.

Sun Y Y Zhu D D Chen F F Qian M M Wei H H Chen W W Xu J J

Oncogene 20160111 33

Most tumors initially respond to cytotoxic treatments, but acquired resistance often follows. The tumor microenvironment (TME) is a major barrier to clinical success by compromising therapeutic efficacy, and pathological relevance of multiple soluble factors released by a therapeutically remodeled TME remains largely unexplored. Here we show that the secreted frizzled-related protein 2 (SFRP2), a Wnt pathway modulator, is produced by human primary fibroblasts after genotoxic treatments. SFRP2 in ...[more]

PMID: 26751775

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Project description:Therapeutic targeting of tumor vulnerabilities is emerging as a key area of research. This review is focused on exploiting the vulnerabilities of tumor cells and the immune cells in the tumor immune microenvironment (TIME), including tumor hypoxia, tumor acidity, the bidirectional proton-coupled monocarboxylate transporters (MCTs) of lactate, mitochondrial oxidative phosphorylation (OXPHOS), and redox enzymes in the tricarboxylic acid cycle. Cancer cells use glucose for energy even under normoxic conditions. Although cancer cells predominantly rely on glycolysis, many have fully functional mitochondria, suggesting that mitochondria are a vulnerable target organelle in cancer cells. Thus, one key distinction between cancer and normal cell metabolism is metabolic reprogramming. Mitochondria-targeted small molecule inhibitors of OXPHOS inhibit tumor proliferation and growth. Another hallmark of cancer is extracellular acidification due lactate accumulation. Emerging results show that lactate acts as a fuel for mitochondrial metabolism and supports tumor proliferation and growth. Metabolic reprogramming occurs in glycolysis-deficient tumor phenotypes and in kinase-targeted, drug-resistant cancers overexpressing OXPHOS genes. Glycolytic cancer cells located away from the vasculature overexpress MCT4 transporter to prevent overacidification by exporting lactate, and the oxidative cancer cells located near the vasculature express MCT1 transporter to provide energy through incorporation of lactate into the tricarboxylic acid cycle. MCTs are, therefore, a vulnerable target in cancer metabolism. MCT inhibitors exert synthetic lethality in combination with metformin, a weak inhibitor of OXPHOS, in cancer cells. Simultaneously targeting multiple vulnerabilities within mitochondria shows synergistic antiproliferative and antitumor effects. Developing tumor-selective, small molecule inhibitors of OXPHOS with a high therapeutic index is critical to fully exploiting the mitochondrial vulnerabilities. We and others developed small-molecule inhibitors containing triphenylphosphonium cation that potently inhibit OXPHOS in tumor cells and tissues. Factors affecting tumor cell vulnerabilities also impact immune cells in the TIME. Glycolytic tumor cells supply lactate to the tumor-suppressing regulatory T cells overexpressing MCTs. Therapeutic opportunities for targeting vulnerabilities in tumor cells and the TIME, as well as the implications on cancer health disparities and cancer treatment, are addressed.

Dataset Information

SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment.

Publications

SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment.

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