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Intratumor δ-catenin heterogeneity driven by genomic rearrangement dictates growth factor dependent prostate cancer progression

Oncogene volume 39, pages 4358–4374 (2020)Cite this article

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Abstract

Only a small number of genes are bona fide oncogenes and tumor suppressors such as Ras, Myc, β-catenin, p53, and APC. However, targeting these cancer drivers frequently fail to demonstrate sustained cancer remission. Tumor heterogeneity and evolution contribute to cancer resistance and pose challenges for cancer therapy due to differential genomic rearrangement and expression driving distinct tumor responses to treatments. Here we report that intratumor heterogeneity of Wnt/β-catenin modulator δ-catenin controls individual cell behavior to promote cancer. The differential intratumor subcellular localization of δ-catenin mirrors its compartmentalization in prostate cancer xenograft cultures as result of mutation-rendered δ-catenin truncations. Wild-type and δ-catenin mutants displayed distinct protein interactomes that highlight rewiring of signal networks. Localization specific δ-catenin mutants influenced p120ctn-dependent Rho GTPase phosphorylation and shifted cells towards differential bFGF-responsive growth and motility, a known signal to bypass androgen receptor dependence. Mutant δ-catenin promoted Myc-induced prostate tumorigenesis while increasing bFGF-p38 MAP kinase signaling, β-catenin-HIF-1α expression, and the nuclear size. Therefore, intratumor δ-catenin heterogeneity originated from genetic remodeling promotes prostate cancer expansion towards androgen independent signaling, supporting a neomorphism model paradigm for targeting tumor progression.

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Fig. 1: Differential δ-catenin distribution patterns in the same prostate tumor mass and prostate cancer (PCa) xenograft cell line.
Fig. 2: δ-Catenin genetic alterations and nonoverlapping interactomes involving distinct biological processes elicited by wild-type and mutant forms of δ-catenin in human PCa.
Fig. 3: Differential δ-catenin subcellular distribution corresponds to the different fate of E-cadherin/p120ctn and influences the interactions of p120ctn with RhoA, Cdc42, and Rac1.
Fig. 4: Differential δ-catenin distribution in PCa cells elicits different responses to bFGF stimulation.
Fig. 5: δ-Catenin promotes prostate tumor development in a mutation dependent manner.
Fig. 6: δ-Catenin mutations enhance β-catenin, Myc, and HIF-1α expression.
Fig. 7: Schematic showing the model of intratumor heterogeneity of δ-catenin in modulation of PCa cell dissemination.

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Acknowledgements

We thank George W. Lanford and William Guiler for technical assistance. This work was supported in part by grants from USA National Cancer Institute CA111891 (QL), CA165202 (QL), the Harriet and John Wooten Foundation for Alzheimer’s and Neurodegenerative Diseases Research (QL), and Chinese Beijing Natural Science Foundation 7172068 (YGJ). This research is based in part upon work conducted using the UNC Proteomics Core Facility, which is supported in part by USA National Cancer Institute P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center.

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Author notes

  1. These authors contributed equally: Mingchuan Li, Jongdee Nopparat

  2. Co-corresponding authors: Qun Lu, Yongguang Jiang

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA

    Mingchuan Li, Jongdee Nopparat, Byron J. Aguilar, Yan-hua Chen, Jiao Zhang, Christi Boykin & Qun Lu

  2. Department of Urological Surgery, Beijing An Zhen Hospital, Capital Medical University, Beijing, 100029, China

    Mingchuan Li, Yong Luo & Yongguang Jiang

  3. Department of Anatomy, Prince of Songkla University, Songkhla, 90110, Thailand

    Jongdee Nopparat

  4. Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Beijing, 100029, China

    Jie Du

  5. Dept. of Urology, The Seventh Medical Center of PLA General Hospital, Beijing, 100029, China

    Xin Ai

  6. The Harriet and John Wooten Laboratory for Alzheimer’s and Neurodegenerative Diseases Research, The Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA

    Qun Lu

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Contributions

QL conceived the project. QL, YGJ, YHC, JD, and XA co-designed the collaboration and experiments. MCL, JN, JZ, BJA, CB, YHC, YL, YGJ, and QL performed experiments and data analyses. All authors contributed to the discussion section and approved the paper for submission.

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Li, M., Nopparat, J., Aguilar, B.J. et al. Intratumor δ-catenin heterogeneity driven by genomic rearrangement dictates growth factor dependent prostate cancer progression. Oncogene 39, 4358–4374 (2020). https://doi.org/10.1038/s41388-020-1281-9

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