DataSheet1_Fallopian tube secreted protein affects ovarian metabolites in high grade serous ovarian cancer.pdf

High grade serous ovarian cancer (HGSOC), the most lethal histotype of ovarian cancer, frequently arises from fallopian tube epithelial cells (FTE). Once transformed, tumorigenic FTE often migrate specifically to the ovary, completing the crucial primary metastatic step and allowing the formation of the ovarian tumors after which HGSOC was originally named. As only the fimbriated distal ends of the fallopian tube that reside in close proximity to the ovary develop precursor lesions such as serous tubal intraepithelial carcinomas, this suggests that the process of transformation and primary metastasis to the ovary is impacted by the local microenvironment. We hypothesize that chemical cues, including small molecules and proteins, may help stimulate the migration of tumorigenic FTE to the ovary. However, the specific mediators of this process are still poorly understood, despite a recent growth in interest in the tumor microenvironment. Our previous work utilized imaging mass spectrometry (IMS) to identify the release of norepinephrine (NE) from the ovary in co-cultures of tumorigenic FTE cells with an ovarian explant. We predicted that tumorigenic FTE cells secreted a biomolecule, not produced or produced with low expression by non-tumorigenic cells, that stimulated the ovary to release NE. As such, we utilized an IMS mass-guided bioassay, using NE release as our biological marker, and bottom-up proteomics to demonstrate that a secreted protein, SPARC, is a factor produced by tumorigenic FTE responsible for enhancing release of ovarian NE and influencing primary metastasis of HGSOC. This discovery highlights the bidirectional interplay between different types of biomolecules in the fallopian tube and ovarian microenvironment and their combined roles in primary metastasis and disease progression.

高级别浆液性卵巢癌（High grade serous ovarian cancer, HGSOC）是致死性最高的卵巢癌组织学亚型，通常起源于输卵管上皮细胞（fallopian tube epithelial cells, FTE）。转化后的致瘤性FTE往往会特异性迁移至卵巢，完成关键的初次转移步骤，进而形成卵巢肿瘤——这也是HGSOC最初得以命名的缘由。
仅紧邻卵巢的输卵管伞部远端会形成浆液性输卵管上皮内癌等前驱病变，这提示致瘤转化及向卵巢的初次转移过程会受到局部微环境的影响。我们提出假说：包括小分子与蛋白质在内的化学信号分子，或可促进致瘤性FTE向卵巢的迁移。尽管近年来肿瘤微环境领域的研究热度持续攀升，但该过程的具体介导因子仍未得到充分阐释。
我们此前的研究借助成像质谱法（imaging mass spectrometry, IMS），在致瘤性FTE细胞与卵巢外植体（ovarian explant）的共培养体系中，检测到卵巢可释放去甲肾上腺素（norepinephrine, NE）。我们推测，致瘤性FTE细胞会分泌一种非致瘤性细胞不表达或低表达的生物分子，该分子可刺激卵巢释放NE。基于此，我们采用以NE释放为生物学标志物的成像质谱导向生物分析法，并结合自下而上蛋白质组学（bottom-up proteomics），证实致瘤性FTE分泌的分泌型酸性富半胱氨酸蛋白（Secreted Protein Acidic and Rich in Cysteine, SPARC）是增强卵巢NE释放、影响HGSOC初次转移的关键因子。
这一发现揭示了输卵管与卵巢微环境中不同类型生物分子间的双向互作，以及二者在初次转移与疾病进展中的协同作用。