TIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer
Open Access
- 17 September 2021
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 218 (11)
- https://doi.org/10.1084/jem.20210911
Abstract
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.Funding Information
- Wilhelm Sander-Stiftung (2016.124.1, 2016.124.2)
- Deutsche Forschungsgemeinschaft (KR2047/8-1)
- Deutsches Zentrum für Infektionsforschung (TI07.001)
- Princess Margaret Cancer Foundation
- European Molecular Biology Organization (ALTF 116-2018)
- Alexander von Humboldt-Stiftung Foundation (DEU 1199182 FLF-P)
- Deutsche Forschungsgemeinschaft (329628492 – SFB 1321)
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