Open AccessTIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer
Author(s) -
Chris D. Hermann,
Benjamin Schoeps,
Celina Eckfeld,
Enkhtsetseg Munkhbaatar,
Lukas Kniep,
Olga Prokopchuk,
Nils Wirges,
Katja Steiger,
Daniel Häußler,
Percy A. Knolle,
Emily Poulton,
Rama Khokha,
Barbara Grünwald,
İhsan Ekin Demir,
Achim Krüger
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20210911
Subject(s) - timp1 , metastasis , pancreatic cancer , medicine , liver cancer , colorectal cancer , oncology , cancer , biology , cancer research , endocrinology , gene expression , gene , genetics
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.