Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis

Abstract

Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies.

Influencing the Tumor Microenvironment: A Phase II Study of Copper Depletion Using Tetrathiomolybdate in Patients with Breast Cancer at High Risk for Recurrence and in Preclinical Models of Lung Metastases

“…Collagen fibers were quantified using ImageJ. Multiphoton second harmonic generation (SHG) imaging was used to characterize collagen quantity and collagen fiber length in rehydrated cross-sections of lungs using a custom-built multiphoton microscope as described previously (46).…”

Stromal cell cadherin-11 regulates adipose tissue inflammation and diabetes

“…In addition, cadherin-11 blockade may be relevant to other diseases linked by ECM deposition by cadherin-11-expressing fibroblasts or myofibroblasts. A recent study showed that obesity increases myofibroblasts and ECM stiffness in the adipose tissue of mammary fat and that changes in ECM mechanics promote breast tumorigenesis in obesity (49). It would be interesting to determine whether blocking cadherin-11 in the myofibroblasts of mammary fat can reduce the risk for breast tumorigenesis by inhibiting obesity-induced collagen production.…”

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…The diverse microarchitectures of fibrillar collagen and the range of resulting biomechanics can result in very different microenvironments despite equivalent levels of collagen [83][84][85], which potentially explains the weak clinical link between collagen I and prognosis in older studies [86,87]. It remains difficult to decouple the effects of fiber diameter, pore size and biomechanics, but it appears that all three act on cells (reviewed in [88]).…”