Project Grant F31CA301931

THE ROLE OF THE MAMMARY FAT PAT IN OBESITY-LINKED BREAST CANCER METASTASIS - BREAST CANCER (BC) IS THE MOST COMMON CANCER IN WOMEN, AND OBESITY IS ASSOCIATED WITH AN INCREASE IN BC METASTASIS IN BOTH PRE- AND POST-MENOPAUSAL WOMEN; HOWEVER, THE MECHANISMS MEDIATING THIS INCREASE REMAIN POORLY UNDERSTOOD. METASTASIS FORMATION DEPENDS ON A CANCER CELL LEAVING THE PRIMARY SITE, MIGRATING THROUGH THE BLOODSTREAM, AND ESTABLISHING NEW GROWTH IN A DISTANT SITE. BOTH METASTATIC CELL-INTRINSIC AND METASTATIC SITE- DEPENDENT FACTORS HELP TO REGULATE THE SUCCESS OF THIS PROCESS; HOWEVER, IT IS UNKNOWN WHETHER OBESITY-LINKED METASTASIS DEPENDS ON CHANGES TO THE METASTASIZING CELL AND/OR CHANGES TO THE DISTANT METASTATIC SITE. MY DATA DEMONSTRATE THAT AN OBESE METASTATIC SITE IS NOT SUFFICIENT TO INCREASE METASTASIS, AS OBESE MICE DO NOT EXPERIENCE INCREASED RATES OF EXPERIMENTAL METASTASIS. CRITICALLY, I HAVE DISCOVERED THAT GROWTH IN AN OBESE PRIMARY TUMOR IS SUFFICIENT TO PROGRAM BREAST CANCER CELLS FOR INCREASED EXPERIMENTAL METASTASIS IN VIVO AND FOR INCREASED MIGRATION AND INVASION IN VITRO. FURTHERMORE, BREAST CANCER CELLS GROWN IN LEAN VS. OBESE PRIMARY TUMORS SHOW DIFFERENTIAL REGULATION OF CELL ADHESION, MIGRATION, AND INVASION, SUGGESTING THAT THE OBESE TUMOR MICROENVIRONMENT ACTS ON BREAST CANCER CELLS TO MODULATE ADHESIVENESS, THEREBY ALLOWING FOR INCREASED MIGRATION, INVASION, AND METASTASIS. I HAVE FURTHER IDENTIFIED THAT MATURE ADIPOCYTES IN THE TUMOR MICROENVIRONMENT ARE SUFFICIENT TO PROGRAM THE METASTATIC POTENTIAL OF BREAST CANCER CELLS. SPECIFICALLY, OBESE ADIPOCYTES SECRETE A MOLECULE(S) WHICH PROMOTES BREAST CANCER CELL MIGRATION, WHILE LEAN ADIPOCYTES SECRETE A MOLECULE(S) WHICH INHIBITS MIGRATION AND PROMOTES ADHESION. I THEREFORE HYPOTHESIZE THAT MATURE ADIPOCYTES IN THE PRIMARY TUMOR MICROENVIRONMENT ACT ON BREAST CANCER CELLS IN A PARACRINE MANNER TO MODULATE METASTATIC POTENTIAL. SPECIFICALLY, IN A LEAN TUMOR MICROENVIRONMENT, THE ADIPOCYTES PROMOTE ADHESION, THEREBY INHIBITING THE MIGRATORY POTENTIAL OF BREAST CANCER CELLS. CONVERSELY, ADIPOCYTES IN AN OBESE SETTING PROMOTE DECREASED ADHESION AND INCREASED MIGRATION. I PROPOSE THAT THE COMBINATION OF THESE TWO FACTORS CONTRIBUTES TO OBESITY- LINKED BREAST CANCER METASTASIS, BOTH THROUGH THE METASTASIS-PROMOTING EFFECTS OF OBESE ADIPOCYTES AND THROUGH THE LOSS OF THE METASTASIS-INHIBITING EFFECTS FROM LEAN ADIPOCYTES. THIS WORK WILL BE CONDUCTED UNDER THE GUIDANCE OF MY SPONSOR, DR. KEREN HILGENDORF, AND CO-SPONSOR, DR. ALANA WELM, BOTH OF WHOM SPECIALIZE IN BREAST CANCER RESEARCH. MY THESIS COMMITTEE IS COMPOSED OF INTERDISCIPLINARY RESEARCHERS WHOSE SPECIALTIES PERTAIN TO DIFFERENT PORTIONS OF THIS PROPOSAL, SUCH AS CELL SIGNALING, METASTASIS, AND THE TUMOR MICROENVIRONMENT. TOGETHER, THESE MENTORS WILL PROVIDE EXPERT GUIDANCE IN ALL FACETS OF THIS PROJECT. IN ADDITION, THIS PROJECT WILL BE SUPPORTED BY MULTIPLE CORE FACILITIES, INCLUDING THOSE THAT OFFER SERVICES IN MICROSCOPY, FLOW CYTOMETRY, LIPIDOMICS, AND IN VIVO STUDIES, WHICH WILL OFFER EXCELLENT SUPPORT AND TRAINING SERVICES TO FACILITATE MY GROWTH AS A RESEARCHER. THE TRAINING PLAN PRESENTED HERE WAS DEVELOPED TO ULTIMATELY PREPARE ME FOR A FUTURE IN ACADEMIA AS AN INDEPENDENT RESEARCHER IN THE FIELD TUMOR MICROENVIRONMENT.