TY - JOUR
T1 - TIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer
AU - Hermann, Chris D.
AU - Schoeps, Benjamin
AU - Eckfeld, Celina
AU - Munkhbaatar, Enkhtsetseg
AU - Kniep, Lukas
AU - Prokopchuk, Olga
AU - Wirges, Nils
AU - Steiger, Katja
AU - Häußler, Daniel
AU - Knolle, Percy
AU - Poulton, Emily
AU - Khokha, Rama
AU - Grünwald, Barbara T.
AU - Demir, Ihsan Ekin
AU - Krüger, Achim
N1 - Publisher Copyright:
© 2021 Hermann et al.
PY - 2021/9/17
Y1 - 2021/9/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85116563511&partnerID=8YFLogxK
U2 - 10.1084/jem.20210911
DO - 10.1084/jem.20210911
M3 - Article
C2 - 34533565
AN - SCOPUS:85116563511
SN - 0022-1007
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
M1 - e20210911
ER -
