PMID- 33848267
OWN - NLM
STAT- MEDLINE
DCOM- 20211005
LR  - 20211005
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 131
IP  - 10
DP  - 2021 May 17
TI  - Myeloid cell-derived PROS1 inhibits tumor metastasis by regulating inflammatory 
      and immune responses via IL-10.
LID - 126089 [pii]
LID - 10.1172/JCI126089 [doi]
LID - e126089
AB  - Stimulation of TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases promotes 
      tumor progression through numerous cellular mechanisms. TAM cognate ligands GAS6 
      and PROS1 (for TYRO3 and MERTK) are secreted by host immune cells, an interaction 
      which may support tumor progression. Here, we revealed an unexpected 
      antimetastatic role for myeloid-derived PROS1: suppressing metastatic potential 
      in lung and breast tumor models. Pros1 deletion in myeloid cells led to increased 
      lung metastasis, independent of primary tumor infiltration. PROS1-cKO bone 
      marrow-derived macrophages (BMDMs) led to elevated TNF-alpha, IL-6, Nos2, and IL-10 
      via modulation of the Socs3/NF-kappaB pathway. Conditioned medium from cKO BMDMs 
      enhanced EMT, ERK, AKT, and STAT3 activation within tumor cells and promoted 
      IL-10-dependent invasion and survival. Macrophages isolated from metastatic lungs 
      modulated T cell proliferation and function, as well as expression of 
      costimulatory molecules on DCs in a PROS1-dependent manner. Inhibition of MERTK 
      kinase activity blocked PROS1-mediated suppression of TNF-alpha and IL-6 but not 
      IL-10. Overall, using lung and breast cancer models, we identified the 
      PROS1/MERTK axis within BMDMs as a potent regulator of adaptive immune responses 
      with a potential to suppress metastatic seeding and revealed IL-10 regulation by 
      PROS1 to deviate from that of TNF-alpha and IL-6.
FAU - Maimon, Avi
AU  - Maimon A
AD  - The Institute for Dental Sciences, Faculty of Dental Medicine and.
FAU - Levi-Yahid, Victor
AU  - Levi-Yahid V
AD  - The Institute for Dental Sciences, Faculty of Dental Medicine and.
FAU - Ben-Meir, Kerem
AU  - Ben-Meir K
AD  - The Lautenberg Center for Immunology and Cancer Research, Israel-Canada Medical 
      Research Institute, Faculty of Medicine, the Hebrew University, Jerusalem, 
      Israel.
FAU - Halpern, Amit
AU  - Halpern A
AD  - The Institute for Dental Sciences, Faculty of Dental Medicine and.
FAU - Talmi, Ziv
AU  - Talmi Z
AD  - The Institute for Dental Sciences, Faculty of Dental Medicine and.
FAU - Priya, Shivam
AU  - Priya S
AD  - The Institute for Dental Sciences, Faculty of Dental Medicine and.
FAU - Mizraji, Gabriel
AU  - Mizraji G
AD  - The Institute for Dental Sciences, Faculty of Dental Medicine and.
FAU - Mistriel-Zerbib, Shani
AU  - Mistriel-Zerbib S
AD  - The Lautenberg Center for Immunology and Cancer Research, Israel-Canada Medical 
      Research Institute, Faculty of Medicine, the Hebrew University, Jerusalem, 
      Israel.
FAU - Berger, Michael
AU  - Berger M
AD  - The Lautenberg Center for Immunology and Cancer Research, Israel-Canada Medical 
      Research Institute, Faculty of Medicine, the Hebrew University, Jerusalem, 
      Israel.
FAU - Baniyash, Michal
AU  - Baniyash M
AD  - The Lautenberg Center for Immunology and Cancer Research, Israel-Canada Medical 
      Research Institute, Faculty of Medicine, the Hebrew University, Jerusalem, 
      Israel.
FAU - Loges, Sonja
AU  - Loges S
AD  - Division of Personalized Medical Oncology (A420), German Cancer Research Center 
      (DKFZ), Heidelberg, Germany.
AD  - Department of Personalized Oncology, University Hospital Mannheim, Mannheim, 
      Germany.
FAU - Burstyn-Cohen, Tal
AU  - Burstyn-Cohen T
AD  - The Institute for Dental Sciences, Faculty of Dental Medicine and.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (IL10 protein, mouse)
RN  - 0 (Interleukin-6)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Pros1 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (interleukin-6, mouse)
RN  - 130068-27-8 (Interleukin-10)
SB  - IM
MH  - Animals
MH  - Calcium-Binding Proteins/genetics/*immunology
MH  - Female
MH  - Interleukin-10/genetics/*immunology
MH  - Interleukin-6/genetics/immunology
MH  - Lung Neoplasms/genetics/*immunology
MH  - Mammary Neoplasms, Experimental/genetics/*immunology
MH  - Mice
MH  - Neoplasm Metastasis
MH  - Neoplasm Proteins/genetics/*immunology
MH  - Tumor Necrosis Factor-alpha/genetics/immunology
MH  - Tumor-Associated Macrophages/*immunology
PMC - PMC8121514
OTO - NOTNLM
OT  - Inflammation
OT  - Macrophages
OT  - Oncology
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists.
EDAT- 2021/04/14 06:00
MHDA- 2021/10/06 06:00
PMCR- 2021/08/17
CRDT- 2021/04/13 17:12
PHST- 2018/11/12 00:00 [received]
PHST- 2021/04/07 00:00 [accepted]
PHST- 2021/04/14 06:00 [pubmed]
PHST- 2021/10/06 06:00 [medline]
PHST- 2021/04/13 17:12 [entrez]
PHST- 2021/08/17 00:00 [pmc-release]
AID - 126089 [pii]
AID - 10.1172/JCI126089 [doi]
PST - ppublish
SO  - J Clin Invest. 2021 May 17;131(10):e126089. doi: 10.1172/JCI126089.