title: 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-κB (NF-κB) complex, a property shared by several effectors of the DNA damage secretory program. Instead of directly altering canonical Wnt signaling, SFRP2 augments β-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.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.|Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Department of Medicine and VAPSHCS, University of Washington, Seattle, WA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: D
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: F
authors.initials: F
authors.lastname: Chen
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Qian
authors.affiliation: Department of Pharmacology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction / Q000502:physiology*; D059016:Tumor Microenvironment / Q000502:physiology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008565:Membrane Proteins; D016328:NF-kappa B; D051153:Wnt Proteins; D051176:beta Catenin; C501126:DKK1 protein, human; C555475:LRP6 protein, human; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C417262:WNT16 protein, human