The Reign of Follistatin in Tumors and Their Microenvironment: Implications for Drug Resistance

Simple Summary Within the extracellular milieu surrounding cancer cells exists an ecosystem of heterogeneous cell populations that dictate tumor growth and survival via cell-cell signaling induced by secreted factors. The transforming growth factor-beta (TGF-beta) superfamily, a crucial programmer of the tumor microenvironment, presents challenges as a therapeutic target due to its biphasic effects in cancer. Despite concerted efforts, the clinical efficacy of its antagonists remains elusive, reflecting a limited understanding of how cancer cells can become nonresponsive to the potent cytostatic effects of these ligands while retaining their tumor promoting effects. Follistatin, a secreted glycoprotein and an endogenous bioneutralizer of TGF-beta ligands, has gained prominence and emerged as a potentially targetable modulator of key resident cell populations in the tumor microenvironment, particularly in squamous cell carcinoma. We delve deeper into the expression patterns and mechanistic role of follistatin in cancer, examining its intimate relationship with TGF-beta and its implications in drug resistance across lung, ovarian, and head and neck cancers.Abstract Follistatin (FST) is a potent neutralizer of the transforming growth factor-beta superfamily and is associated with normal cellular programs and various hallmarks of cancer, such as proliferation, migration, angiogenesis, and immune evasion. The aberrant expression of FST by solid tumors is a well-documented observation, yet how FST influences tumor progression and therapy response remains unclear. The recent surge in omics data has revealed new insights into the molecular foundation underpinning tumor heterogeneity and its microenvironment, offering novel precision medicine-based opportunities to combat cancer. In this review, we discuss these recent FST-centric studies, thereby offering an updated perspective on the protean role of FST isoforms in shaping the complex cellular ecosystem of tumors and in mediating drug resistance.