Subclonal β-catenin/YAP signaling heterogeneity accelerates ovarian cancer metastasis through a senescence-associated secretory phenotype

Area of Science:

• Oncology
• Cancer Biology
• Metastasis Research

Background:

• Intratumoral heterogeneity complicates cancer treatment.
• Distinct tumor subclones have varying drug sensitivities and metastatic potential.
• Mechanisms of subclone interaction in metastasis are poorly understood.

Purpose of the Study:

• To investigate the role of β-catenin signaling heterogeneity in ovarian cancer metastasis.
• To elucidate the mechanisms of cooperative interaction between distinct tumor subclones.
• To identify potential therapeutic targets for metastatic ovarian cancer.

Main Methods:

• Utilized an isogenic ovarian cancer cell pair with differential β-catenin signaling (non-metastatic vs. highly metastatic).
• Co-engrafted NM and HM cells in vivo and analyzed peritoneal metastasis.
• Performed immunohistochemical analysis and investigated senescence-associated secretory phenotype (SASP) driven by Hippo/YAP signaling.

Main Results:

• Co-engraftment of NM and HM cells synergistically enhanced peritoneal metastasis.
• β-catenin heterogeneity was observed in mixed tumors, mimicking clinical cases.
• Both NM cells and β-catenin-knockout HM cells exhibited SASP, driven by Hippo/YAP signaling.
• SASP facilitated metastasis of β-catenin-high subclones via paracrine signaling.
• Mixed tumors showed increased susceptibility to fisetin (senolytic agent) and YAP inhibition, reducing metastatic burden.

Conclusions:

• Pre-existence of senescence-like tumor cells contributes to untreated ovarian cancer progression.
• β-catenin heterogeneity drives ovarian cancer progression through SASP-mediated subclonal interactions.
• Targeting intratumoral communication via senolytic agents or YAP inhibition offers therapeutic potential for metastatic ovarian cancer.