Thrombospondin 2（THBS2）表現之癌症相關成纖維細胞驅動結直腸息肉的惡性轉化

Abstract

結直腸息肉是結直腸癌（CRC）的前驅病變，了解其分子異質性有助於揭示結直腸癌早期惡性轉化的機制。本研究收集18例結直腸息肉及5例正常黏膜樣本，進行轉錄體分析。結果顯示，息肉在基因表現、路徑活化與腫瘤微環境（TME）組成上呈現出與CMS2型與CMS4型結直腸癌相似的二元分化特徵。其中，我們發現THBS2為驅動上皮–間質轉化（EMT）的關鍵因子，其透過 integrin αVβ3–FAK訊號通路發揮作用，且其表現量與息肉癌症率呈正相關 (R2 = 0.84，P = 0.03)。泛癌分析支持 THBS2 為結直腸息肉與癌症的預後標誌。單細胞轉錄體分析進一步揭示出一群具特徵性的 THBS2⁺ 癌相關纖維母細胞（CAF），參與腫瘤微環境中早期的細胞外基質（ECM）重塑。體外實驗證實，rhTHBS2及Thbs2過表達之條件培養基（CM）促進CMS4大腸癌細胞Caco-2及HCT116的腫瘤形成、跨膜遷移及侵襲能力。值得注意的是，藉由藥物重定位所辨識出的 GW0742 能抑制rhTHBS2造成的細胞遷移。整合mRNA、lncRNA、miRNA、circRNA的WGCNA分析指出，ncRNA參與THBS2調控的惡性轉型。綜上所述，CRC 的預後可能在癌症發生前即已被THBS2⁺ CAF 所主導的腫瘤微環境塑形，並指出THBS2及其調控網路為早期干預與預後評估的潛在標誌物。

Colorectal polyps are precancerous lesions of CRC, yet their molecular heterogeneity and links to CRC subtypes remain unclear. We analyzed bulk transcriptomes of 18 colorectal polyps and 5 normal controls, revealing a dichotomous pattern in gene expression, pathway activation, and TME composition resembling CMS2 and CMS4 CRC. THBS2 drives EMT via integrin αVβ3–FAK and correlates with polyp cancer rates (R² = 0.84, P = 0.03). Pan-cancer analyses supported THBS2 as a prognostic marker for both polyps and CRC. Single-cell transcriptomics further revealed a distinct THBS2⁺ cancer-associated fibroblast (CAF) population implicated in early extracellular matrix (ECM) remodeling within the TME. In vitro, rhTHBS2/Thbs2 OE fibroblast CM promotes tumorigenesis, migration and invasion in CMS4 CRC cells; while GW0742, a drug identified through repurposing, reverses these effects. Integrative WGCNA of multi-RNA reveals ncRNA networks underpinning THBS2-driven transformation. These findings suggest that CRC prognostic fate may be preconfigured by THBS2⁺ CAFs before cancer onset and nominate THBS2 and its regulatory circuit as early biomarkers and therapeutic targets.