JAG1-Mediated Signaling Promotes Lymph Node Metastasis in Breast Cancer
Session Number
Project ID: MEDH 39
Advisor(s)
Benjamin Gordon; University of Illinois Chicago (UIC)
Discipline
Medical and Health Sciences
Start Date
19-4-2023 10:20 AM
End Date
19-4-2023 10:35 AM
Abstract
Breast cancer (BC) patients have better outcomes when cancer is detected early, but metastasis remains a major cause of mortality. High levels of the Notch ligand JAGGED-1 (JAG1) has been linked with poor BC prognosis, and is associated with drug resistance and tumor recurrence. Furthermore, JAG1 is associated with lymph node (LN) metastasis, which is a reliable prognostic indicator. While these clinical correlations suggest that JAG1 plays a significant role in BC progression and metastasis, the exact process by which it occurs is not fully comprehended. We hypothesize that JAG1 promotes lymph node metastasis by signaling to lymphatic endothelial cells via Notch signaling. To test our hypothesis, we utilized multiple JAG1-high and matched low/negative breast cancer cell lines and injected them into the fourth mammary fat pads of mice. We then collected tumor-draining LNs, sectioned them, and then stained pancytokeratin to identify metastatic cancer cells. We also utilized lymphatic markers to identify regions of the LNs in which cancer cells invaded. After conducting microscopy analyses of LN sub-anatomical regions and peripheral lymphatic vasculature, we scored tumor invasion into lymphatic vessels outside of the LN (lymphovascular invasion) and metastasis within the LN. The results show that JAG1 promotes LN metastasis and lymphovascular invasion to the primary draining LN of the tumor in immunocompetent mice. These findings suggest a new function of JAG1 in promoting lymphovascular invasion, and targeting JAG1-mediated signaling may be a potential therapeutic strategy for preventing or slowing LN metastasis in breast cancer patients.
JAG1-Mediated Signaling Promotes Lymph Node Metastasis in Breast Cancer
Breast cancer (BC) patients have better outcomes when cancer is detected early, but metastasis remains a major cause of mortality. High levels of the Notch ligand JAGGED-1 (JAG1) has been linked with poor BC prognosis, and is associated with drug resistance and tumor recurrence. Furthermore, JAG1 is associated with lymph node (LN) metastasis, which is a reliable prognostic indicator. While these clinical correlations suggest that JAG1 plays a significant role in BC progression and metastasis, the exact process by which it occurs is not fully comprehended. We hypothesize that JAG1 promotes lymph node metastasis by signaling to lymphatic endothelial cells via Notch signaling. To test our hypothesis, we utilized multiple JAG1-high and matched low/negative breast cancer cell lines and injected them into the fourth mammary fat pads of mice. We then collected tumor-draining LNs, sectioned them, and then stained pancytokeratin to identify metastatic cancer cells. We also utilized lymphatic markers to identify regions of the LNs in which cancer cells invaded. After conducting microscopy analyses of LN sub-anatomical regions and peripheral lymphatic vasculature, we scored tumor invasion into lymphatic vessels outside of the LN (lymphovascular invasion) and metastasis within the LN. The results show that JAG1 promotes LN metastasis and lymphovascular invasion to the primary draining LN of the tumor in immunocompetent mice. These findings suggest a new function of JAG1 in promoting lymphovascular invasion, and targeting JAG1-mediated signaling may be a potential therapeutic strategy for preventing or slowing LN metastasis in breast cancer patients.