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.
TIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer
Disclosures: O. Prokopchuk reported grants from DZIF (grant TI07.001) during the conduct of the study. K. Steiger reported personal fees from Roche outside the submitted work; in addition, K. Steiger had a patent to a radiopharmaceutical issued and is a member of the advisory board of TRIMT. No other disclosures were reported.
- Award Id(s): 2016.124.1,2016.124.2
- Award Id(s): KR2047/8-1
- Award Id(s): TI07.001
- Award Id(s): ALTF 116-2018
- Award Id(s): DEU 1199182 FLF-P
- Award Id(s): 329628492 – SFB 1321
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Chris D. Hermann, Benjamin Schoeps, Celina Eckfeld, Enkhtsetseg Munkhbaatar, Lukas Kniep, Olga Prokopchuk, Nils Wirges, Katja Steiger, Daniel Häußler, Percy Knolle, Emily Poulton, Rama Khokha, Barbara T. Grünwald, Ihsan Ekin Demir, Achim Krüger; TIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer. J Exp Med 1 November 2021; 218 (11): e20210911. doi: https://doi.org/10.1084/jem.20210911
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