Adipose Tissue from Lean and Obese Mice Induces a Mesenchymal to Epithelial Transition-Like Effect in Triple Negative Breast Cancers Cells Grown in 3-Dimensional Culture

Abstract

Breast cancer is the second leading cause of cancer-related mortality among women globally with obesity being one risk factor. Obese breast cancer patients have at least a 30% increased risk of death from breast cancer compared to non-obese breast cancer patients because they present with larger tumors and generally have increased rates of metastasis. Moreover, obese breast cancer patients respond more poorly to treatment compared to non-obese patients, particularly pre-menopausal women diagnosed with triple negative breast cancer (TNBC). To help understand the molecular mechanisms underlying the increased metastasis associated with obesity, we previously established a three-dimensional culture system that permits the co-culture of adipocytes and TNBC cells in a manner that mimics an in vivo milieu. Using this system, we demonstrate that white adipose tissue from both lean and obese mice can induce a partial mesenchymal-to-epithelial transition (MET). Triple negative breast cancer cells adopt an epithelial morphology and have an increased expression of some epithelial markers, but they maintain the expression of mesenchymal markers, furnishing the breast cancer cells with hybrid properties that are associated with more aggressive tumors. Thus, these data suggest that adipose tissue has the potential to promote secondary tumor formation in lean and obese women. Further work is needed to determine if targeting the partial MET induced by adipose tissue could reduce metastasis.

Obesity: The Fat Tissue Disease Version of Cancer

“…Explorations about these connecting bridges have yielded promising answers, such as the recognition of fat mass and obesity-associated genes (e.g., FTO ) as a common mechanistic basis for both cancer and obesity and the finding that obesity-associated dysmetabolism causes genotoxic stress in favor of cancer comorbidity [ 49 , 50 , 51 ]. This evidence adds to the results from many other in vitro [ 51 , 52 , 53 ], ex vivo [ 54 , 55 ], and in vivo studies [ 56 , 57 , 58 , 59 ] and has been reviewed and acknowledged by the International Agency for Research on Cancer, who announced that there is enough confident and unbiased evidence about the association of excess body weight with a reinforced cancer predisposition—in particular with regard to more than twelve types of cancer in various tissues/organ systems, such as blood, central nervous system, endometrium, esophagus, kidney, pancreas, liver, colon, postmenopausal breast, ovary, gallbladder, and thyroid gland—in agreement with the World Cancer Research Fund/American Institute for Cancer Research [ 58 , 60 ].…”

Adipose Tissue in Breast Cancer Microphysiological Models to Capture Human Diversity in Preclinical Models

“…The other platforms either included 3T3-L1 preadipocytes [ 28 , 53 ] or murine preadipocyte line 3T3-F442A [ 45 ]. As an alternative to trans-well co-culture, Asante et al embedded murine per-uterine and inguinal white adipose tissue (WAT) in Matrigel to collect adipose-derived conditioned media and assess the paracrine effects of lean and obese adipose tissue on MDA-MB-231 mesenchymal–epithelial transition (MET) [ 54 ]. Additional scaffolds, including silk, fibrin, collagen, and decellularized matrices, were used as a trans-well coating or more complex in vitro system to evaluate the role of breast cancer-adipocyte crosstalk on breast cancer progression and invasiveness [ 55 , 56 , 57 , 58 ].…”

Identification of lysyl oxidase as an adipocyte-secreted mediator that promotes a partial mesenchymal-to-epithelial transition in MDA-MB-231 cells

“…Evidence shows that cancer cells can successfully metastasize to other organs without completely reverting to an epithelial-like state [ 26 ]. The metastasizing tumour cells may exhibit a state of phenotypic duality where tumour cells possess both mesenchymal and epithelial properties.…”

“…Cells enduring this transitional process are no longer thought to oscillate between the full epithelial and full mesenchymal states, but rather they move through a spectrum of partial/hybrid/intermediate phases [ 20 ]. Cells in a partial state have both migratory and cell-cell adhesion properties, promoting the formation of migratory clusters to enhance cell plasticity and survival in different microenvironments [ 26 ]. For instance, the multicellular aggregate aids in suppression of senescence and opposition of anoikis, advancing cancer aggression [ 26 , 27 ].…”