Large adipocytes in a biomimetic adipose tissue model promote breast cancer malignancy.

Obesity worsens breast cancer survival but how increased adipocyte size, which typifies obese adipose tissue and correlates with poor prognosis, impacts cancer progression remains unclear. Understanding these connections is challenging as adipocyte size is highly heterogeneous and not tunable with traditional experimental approaches. Here, we develop a biomimetic, engineered adipose tissue model to culture size-sorted adipocytes isolated from the same donor and assess their impact on tumor cell behavior.

Protocol to fabricate elastomer microwells for three-dimensional culture of primary adipocytes.

Our understanding of how adipocytes influence metabolic signaling, immune function, and cancer progression remains limited as the culture of primary adipocytes is challenging. Here, we present a protocol to fabricate elastomer microwells for three-dimensional culture of collagen-embedded adipocytes. We describe steps to cure and functionalize elastomer microwells and to isolate and embed primary adipocytes.

Computational modeling of the physical features that influence breast cancer invasion into adipose tissue.

Breast cancer invasion into adipose tissue strongly influences disease progression and metastasis. The degree of cancer cell invasion into adipose tissue depends on both biochemical signaling and the mechanical properties of cancer cells, adipocytes, and other key components of adipose tissue. We model breast cancer invasion into adipose tissue using discrete element method simulations of active, cohesive spherical particles (cancer cells) invading into confluent packings of deformable polyhedra (adipocytes).

Computational modeling of the physical features that influence breast cancer invasion into adipose tissue.

Breast cancer invasion into adipose tissue strongly influences disease progression and metastasis. The degree of cancer cell invasion into adipose tissue depends on numerous biochemical and physical properties of cancer cells, adipocytes, and other key components of adipose tissue. We model breast cancer invasion into adipose tissue as a physical process by carrying out simulations of active, cohesive spherical particles (cancer cells) invading into confluent packings of deformable polyhedra (adipocytes).

Designing Patient-Driven, Tissue-Engineered Models of Primary and Metastatic Breast Cancer.

The rising survival rate for early-stage breast cancer in the United States has created an expanding population of women in remission at risk for distant recurrence, with metastatic spread to the brain demonstrating an especially poor prognosis. The current standard of care for breast cancer brain metastases is not well defined or differentiated from the treatment of brain metastases from other primary sites. Here, we present tissue-engineered models of the primary and brain metastatic breast cancer microenvironments informed by analysis of patient tumor resections.

Regulation of Tumor Invasion by the Physical Microenvironment: Lessons from Breast and Brain Cancer.

The success of anticancer therapies is often limited by heterogeneity within and between tumors. While much attention has been devoted to understanding the intrinsic molecular diversity of tumor cells, the surrounding tissue microenvironment is also highly complex and coevolves with tumor cells to drive clinical outcomes. Here, we propose that diverse types of solid tumors share common physical motifs that change in time and space, serving as universal regulators of malignancy.

Obesity-associated Adipose Stromal Cells Promote Breast Cancer Invasion Through Direct Cell Contact and ECM Remodeling.

Obesity increases the risk and worsens the prognosis for breast cancer due, in part, to altered adipose stromal cell (ASC) behavior. Whether ASCs from obese individuals increase migration of breast cancer cells relative to their lean counterparts, however, remains unclear. To test this connection, multicellular spheroids composed of MCF10A-derived tumor cell lines of varying malignant potential and lean or obese ASCs were embedded into collagen scaffolds mimicking the elastic moduli of interstitial breast adipose tissue.

Chemoprotection Across the Tumor Border: Cancer Cell Response to Doxorubicin Depends on Stromal Fibroblast Ratios and Interstitial Therapeutic Transport.

Introduction: Increasing evidence suggests that the tumor microenvironment reduces therapeutic delivery and may lead to chemotherapeutic resistance. At tumor borders, drug is convectively transported across a unique microenvironment composed of inverse gradients of stromal and tumor cells. These regions are particularly important to overall survival, as they are often missed through surgical intervention and contain many invading cells, often responsible for metastatic spread.