MUC1 is a tumor-associated antigen involved in oncogenesis, regulation of cellular signaling and transcription and protection of epithelial surfaces. In addition to the widespread expression on epithelia, MUC1 is also found on hematopoietic cells;however, the function of MUC1 in these cells is still fairly unknown. We have found that the lack of Muc1 in primary myeloid progenitors from the C57BL/6 Muc1-/- (KO) mice resulted in an increased expansion of CD11b+Gr1+ cells under GM-CSF and IL-4 signaling, as compared to the wild type (WT) C57BL/6 mice. The CD11b+Gr1+ cells that were expanded in vitro from the KO bone marrow suppressed T cell proliferation in vitro while those from the WT did not, suggesting that these KO CD11b+Gr1+ cells were myeloid derived suppressor cells (MDSCs). MDSCs contribute to the immune suppression frequently seen in cancer;however, the mechanism by which they differentiate from myeloid progenitors is still relatively unknown. Most intriguingly, Muc1 KO mice were able to better tolerate allogeneic tumor growth, with an accumulation of CD11b+Gr1+ cells in the blood and tumor draining lymph nodes. The expansion of CD11b+Gr1+ MDSCs from KO bone marrow was accompanied by beta-catenin down regulation, and inhibition of beta-catenin down regulation could reverse the expansion of CD11b+Gr1+ MDSCs. Our findings indicate a need for Muc1 in modulating the differentiation of myeloid progenitors into CD11b+Gr1+ MDSCs. We hypothesize that MUC1 plays a critical role as a signal transducer in MDSC differentiation in response to a steady state disturbance. To further characterize the mechanistic and functional role of Muc1 in regulating MDSC differentiation, we propose the following specific aims: (1) To determine the mechanism by which Muc1 regulates the differentiation of myeloid progenitors into CD11b+Gr1+ MDSCs, (2) To determine functional significance of MDSCs generated in tumor-bearing Muc1 KO mice by characterizing MDSC populations generated as well as the process by which they develop from the bone marrow and accumulate in the periphery, (3) To determine the effect of a lack of Muc1 in myeloid development during dextran sodium sulfate (DSS)-induced colitis and colitis associated cancer (CAC) by using chimeric mice that lack or have Muc1 in the hematopoietic or non hematopoietic compartment. MUC1 is an especially attractive target for the development of anti-cancer agents, which would be designed to target MUC1 on carcinomas, but could also affect the hematopoietic cells expressing MUC1 and our studies would be useful in continuing to define the role of MUC1 in hematopoiesis. At the same time, furthering our understanding of the signaling pathways involved in MDSC differentiation (MUC1 regulated or otherwise) would enable the targeting of these pathways by drugs in cancer and inflammation more readily. Results from these studies should give us clearer insight into the role of MUC1 in the epithelium and hematopoietic system in both inflammation and cancer signaling pathways.

Public Health Relevance

In this proposal we will study the function of MUC1, a cell-associated signaling mucin, in the maturation and expansion of a cell population (myeloid derived suppressor cells, MDSCs) that can suppress the immune system. Although MUC1 is well established as an oncogene in epithelial tissues, it appears to have different roles in hematopoietic tissues. This study will provide novel mechanistic and functional insights into the immunosuppressive microenvironment that can be found in inflammation and tumors. Further understanding of the signaling pathways involved in MDSC differentiation as well as increased insight into the role of MUC1 in the epithelium and hematopoietic systems in inflammation and cancer will enable us to target therapies more knowledgeably.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064389-19
Application #
8461912
Study Section
Special Emphasis Panel (ZRG1-OTC-K (06))
Program Officer
Howcroft, Thomas K
Project Start
1994-07-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
19
Fiscal Year
2013
Total Cost
$339,542
Indirect Cost
$132,504
Name
Mayo Clinic, Arizona
Department
Type
DUNS #
153665211
City
Scottsdale
State
AZ
Country
United States
Zip Code
85259
Poh, Tze Wei; Madsen, Cathy S; Gorman, Jessica E et al. (2013) Downregulation of hematopoietic MUC1 during experimental colitis increases tumor-promoting myeloid-derived suppressor cells. Clin Cancer Res 19:5039-52
Roy, L D; Sahraei, M; Subramani, D B et al. (2011) MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene 30:1449-59
Petersson, J; Schreiber, O; Hansson, G C et al. (2011) Importance and regulation of the colonic mucus barrier in a mouse model of colitis. Am J Physiol Gastrointest Liver Physiol 300:G327-33
Kinlough, Carol L; Poland, Paul A; Gendler, Sandra J et al. (2011) Core-glycosylated mucin-like repeats from MUC1 are an apical targeting signal. J Biol Chem 286:39072-81
Poh, Tze Wei; Bradley, Judy M; Mukherjee, Pinku et al. (2009) Lack of Muc1-regulated beta-catenin stability results in aberrant expansion of CD11b+Gr1+ myeloid-derived suppressor cells from the bone marrow. Cancer Res 69:3554-62
Hattrup, Christine L; Gendler, Sandra J (2008) Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol 70:431-57
Thompson, Eric J; Shanmugam, Kandavel; Hattrup, Christine L et al. (2006) Tyrosines in the MUC1 cytoplasmic tail modulate transcription via the extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB pathways. Mol Cancer Res 4:489-97
Hattrup, Christine L; Gendler, Sandra J (2006) MUC1 alters oncogenic events and transcription in human breast cancer cells. Breast Cancer Res 8:R37
Mukherjee, P; Tinder, T L; Basu, G D et al. (2005) MUC1 (CD227) interacts with lck tyrosine kinase in Jurkat lymphoma cells and normal T cells. J Leukoc Biol 77:90-9
Al Masri, Azzah; Gendler, Sandra J (2005) Muc1 affects c-Src signaling in PyV MT-induced mammary tumorigenesis. Oncogene 24:5799-808

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