胎児発生メカニズムの一部ががんの進行を助長することを発見(Mechanism in embryonic development makes cancer aggressive)

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2025-05-22 リンショーピング大学 (LiU)

スウェーデンのリンショーピング大学の研究チームは、結腸直腸がん細胞が胚発生時に重要な役割を果たすWntシグナル伝達経路を悪用し、がんの浸潤性と転移性を高めていることを明らかにしました。この経路は、通常、四肢や心臓の形成を制御するTBX3タンパク質と協調して働きますが、がん細胞ではこのメカニズムが再利用され、異常な細胞増殖を引き起こします。Wnt経路の過剰活性は、結腸直腸がんの約80%で見られますが、正常な幹細胞の維持にも不可欠なため、従来の治療ではその抑制が困難でした。今回の研究は、TBX3とWntの相互作用を標的とすることで、正常な幹細胞を損なうことなくがんの進行を抑制する新たな治療法の開発に道を開く可能性があります。この成果は『PNAS』誌に掲載されました。

<関連情報>

大腸癌における発生因子TBX3はWnt/β-カテニン転写複合体と関与し転移遺伝子を制御する The developmental factor TBX3 engages with the Wnt/β-catenin transcriptional complex in colorectal cancer to regulate metastasis genes

Amaia Jauregi-Miguel, Simon Söderholm, Tamina Weiss, +21 , and Claudio Cantù
Proceedings of the National Academy of Sciences  Published:May 9, 2025
DOI:https://doi.org/10.1073/pnas.2419691122

胎児発生メカニズムの一部ががんの進行を助長することを発見(Mechanism in embryonic development makes cancer aggressive)

Significance

Dysregulated Wnt signaling is a well-established driver of colorectal carcinogenesis. However, its pivotal role in normal intestinal stem cell homeostasis has posed significant challenges for its therapeutic inhibition, highlighting the need for discovering cancer-specific mechanisms. Our research reveals that the transcription factor TBX3, long recognized for its role in limb and heart embryogenesis, becomes aberrantly present in colorectal cancers (CRC). In this extraneous context, TBX3 adopts new functions: Instead of binding the DNA as a classic transcription factor, it employs short, conserved motifs on its surface to stick to other protein complexes—including the Wnt machinery—and fosters metastasis-inducing genetic programs. We hypothesize that targeting TBX3 could impair this aberrant embryonic-like behavior without affecting adult homeostasis.

Abstract

Wnt signaling orchestrates gene expression in a plethora of processes during development and adult cell homeostasis via the action of nuclear β-catenin. Yet, little is known about how β-catenin generates context-specific transcriptional outcomes. Understanding this will reveal how aberrant Wnt/β-catenin signaling causes neoplasia specifically of the colorectal epithelium. We have previously identified the transcription factor TBX3 as a tissue-specific component of the Wnt/β-catenin nuclear complex during mouse forelimb development. In this study, we show that TBX3 is functionally active in human colorectal cancer (CRC). Here, genome-wide binding and transcriptomics analyses reveal that TBX3 regulates cancer metastasis genes in cooperation with Wnt/β-catenin. Proteomics proximity labeling performed across Wnt pathway activation shows that TBX3 engages with several transcription factors and chromatin remodeling complexes found at Wnt responsive elements (WRE). Protein sequence and structure analysis of TBX3 revealed short motifs, including an exposed Asn-Pro-Phe (NPF), that mediate these interactions. Deletion of these motifs abrogates TBX3’s proximity to its protein partners and its ability to enhance the Wnt-dependent transcription. TBX3 emerges as a key modulator of the oncogenic activity of Wnt/β-catenin in CRC, and its mechanism of action exposes protein-interaction surfaces as putative druggable targets.

細胞遺伝子工学
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