A Selective β-Catenin-Metadherin/CEACAM1-CCL3 Axis Mediates Metastatic Heterogeneity upon Tumor-Macrophage Interaction

Sally K Y To*, Maggie K S Tang, Yin Tong, Jiangwen Zhang, Karen K L Chan, Philip P C Ip, Jue Shi*, Alice S T Wong*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Tumor heterogeneity plays a key role in cancer relapse and metastasis, however, the distinct cellular behaviors and kinetics of interactions among different cancer cell subclones and the tumor microenvironment are poorly understood. By profiling an isogenic model that resembles spontaneous human ovarian cancer metastasis with an highly metastatic (HM) and non-metastatic (NM) tumor cell pair, one finds an upregulation of Wnt/β-catenin signaling uniquely in HM. Using humanized immunocompetent mice, one shows for the first time that activated β-catenin acts nonautonomously to modulate the immune microenvironment by enhancing infiltrating tumor-associated macrophages (TAM) at the metastatic site. Single-cell time-lapse microscopy further reveals that upon contact with macrophages, a significant subset of HM, but not NM, becomes polyploid, a phenotype pivotal for tumor aggressiveness and therapy resistance. Moreover, HM, but not NM, polarizes macrophages to a TAM phenotype. Mechanistically, β-catenin upregulates cancer cell surface metadherin, which communicates through CEACAM1 expressed on macrophages to produce CCL3. Tumor xenografts in humanized mice and clinical patient samples both corroborate the relevance of enhanced metastasis, TAM activation, and polyploidy in vivo. The results thus suggest that targeting the β-catenin-metadherin/CEACAM1-CCL3 positive feedback cascade holds great therapeutic potential to disrupt polyploidization of the cancer subclones that drive metastasis.

Original languageEnglish
Article number2103230
Number of pages14
JournalAdvanced Science
Volume9
Issue number16
Early online date11 Apr 2022
DOIs
Publication statusPublished - 3 Jun 2022

Scopus Subject Areas

  • Engineering(all)
  • Physics and Astronomy(all)
  • Chemical Engineering(all)
  • Materials Science(all)
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Medicine (miscellaneous)

User-Defined Keywords

  • cytokinesis
  • ovarian cancer
  • polyploid
  • tumor-associated macrophages
  • β-catenin

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