Sex disparity in cancer is so far inadequately considered, and components of its basis are rather unknown. We reveal that male versus female pancreatic cancer (PC) patients and mice show shortened survival, more frequent liver metastasis, and elevated hepatic metastasis-promoting gene expression. Tissue inhibitor of metalloproteinases 1 (TIMP1) was the secreted factor with the strongest male-biased expression in patient-derived pancreatic tumors. Male-specific up-regulation of systemic TIMP1 was demonstrated in PC mouse models and patients. Using TIMP1-competent and TIMP1-deficient PC mouse models, we established a causal role of TIMP1 in determining shortened survival and increased liver metastasis in males. Observing TIMP1 expression as a risk parameter in males led to identification of a subpopulation exhibiting increased TIMP1 levels (T1HI males) in both primary tumors and blood. T1HI males showed increased risk for liver metastasis development not only in PC but also in colorectal cancer and melanoma. This study reveals a lifestyle-independent sex disparity in liver metastasis and may open new avenues toward precision medicine.

中文翻译：

---

TIMP1表达是胰腺癌肝转移和生存性别差异的基础


迄今为止，癌症中的性别差异尚未得到充分考虑，其基础组成部分也相当未知。我们发现，与女性相比，男性胰腺癌（PC）患者和小鼠的生存期更短，肝转移更频繁，并且肝转移促进基因表达升高。金属蛋白酶组织抑制剂 1 (TIMP1) 是患者源性胰腺肿瘤中男性偏向表达最强的分泌因子。 PC 小鼠模型和患者中证实了雄性特异性全身性 TIMP1 上调。使用 TIMP1 有效和 TIMP1 缺陷的 PC 小鼠模型，我们确定了 TIMP1 在确定雄性存活缩短和肝转移增加中的因果作用。观察 TIMP1 表达作为男性的风险参数，结果鉴定出原发肿瘤和血液中 TIMP1 水平升高的亚群（T1HI 男性）。 T1HI男性不仅在PC中而且在结直肠癌和黑色素瘤中表现出肝转移发展的风险增加。这项研究揭示了肝转移中与生活方式无关的性别差异，并可能为精准医学开辟新途径。