ATF4 and FGFR4 cooperatively support thyroid cancer progression and CAF-associated tumor-promoting features

Abstract

Aggressive thyroid cancer remains difficult to treat, partly because molecular programs linking malignant behavior to cancer-associated fibroblast (CAF)-related support are incompletely defined. This study investigated whether ATF4 and FGFR4 cooperate in thyroid cancer cells and whether this relationship persists in a CAF-associated context. Stable ATF4 and/or FGFR4 knockdown was established in 8305 C thyroid cancer cells. Proliferation, migration, invasion, apoptosis, cytokine secretion, transcriptomic changes, and xenograft growth were assessed under basal and CAF-conditioned culture conditions. Silencing ATF4 or FGFR4 reduced 8305 C cell proliferation, migration, and invasion, with the strongest inhibition after combined knockdown. These effects persisted in CAF-conditioned medium and were accompanied by increased apoptosis, reduced IL-6 and TNF-α secretion, and transcriptomic changes involving cell cycle, stress-response, apoptosis, and inflammatory pathways. In vivo, ATF4 and/or FGFR4 silencing suppressed xenograft growth, increased tumor apoptosis, and reduced CAF-associated marker expression. ATF4 and FGFR4 are functionally associated in thyroid cancer progression. Their cooperative program may contribute to cancer cell aggressiveness and to the maintenance of a CAF-associated tumor-promoting microenvironment.