Interplay between hormonal and mechanical signals in mammary morphodynamics.

Mammographic density is a well-established risk factor for breast cancer. In a recent study, Northey et al. reveal that the associated increase in tissue stiffness elevates extracellular signal-regulated kinase (ERK) activity, promoting progesterone receptor-dependent receptor activator of nuclear factor κß (RANK) signaling. Thus, stiffness alters the context of hormonal signaling and increases mammary stem cells. This mechanism suggests potential treatments for breast cancer.

Tissue mechanics coevolves with fibrillar matrisomes in healthy and fibrotic tissues.

Fibrillar proteins are principal components of extracellular matrix (ECM) that confer mechanical properties to tissues. Fibrosis can result from wound repair in nearly every tissue in adults, and it associates with increased ECM density and crosslinking as well as increased tissue stiffness. Such fibrotic tissues are a major biomedical challenge, and an emerging view posits that the altered mechanical environment supports both synthetic and contractile myofibroblasts in a state of persistent activation. Here, we review the matrisome in several fibrotic diseases, as well as normal tissues, with a focus on physicochemical properties. Stiffness generally increases with the abundance of fibrillar collagens, the major constituent of ECM, with similar mathematical trends for fibrosis as well as adult tissues from soft brain to stiff bone and heart development. Changes in expression of other core matrisome and matrisome-associated proteins or proteoglycans contribute to tissue stiffening in fibrosis by organizing collagen, crosslinking ECM, and facilitating adhesion of myofibroblasts. Understanding how ECM composition and mechanics coevolve during fibrosis can lead to better models and help with antifibrotic therapies.

Soft Microenvironments Induce Chemoresistance by Increasing Autophagy Downstream of Integrin-Linked Kinase.

Breast cancer relapse can develop over the course of years as a result of dormant cancer cells that disseminate to secondary sites. These dormant cells are often resistant to conventional hormone and chemotherapy. Although recurrence is the main cause of death from cancer, microenvironmental factors that may influence resistance to therapy and duration of dormancy are largely unknown. Breast cancer relapse is often detected in tissues that are softer than the normal mammary gland or the primary breast tumor, such as bone marrow, brain, and lung. We therefore explored how stiffness of the microenvironment at secondary sites regulates tumor dormancy and the response of breast cancer cells to hormone and chemotherapy. In soft microenvironments reminiscent of metastatic sites, breast cancer cells were more resistant to the estrogen receptor modulator tamoxifen as a result of increased autophagy and decreased expression of estrogen receptor-α. Consistently, pharmacologic inhibition or genetic downregulation of autophagy increased the response of breast cancer cells to tamoxifen on soft substrata. In addition, autophagy was decreased downstream of integrin-linked kinase on stiff substrata. Altogether, our data show that tissue mechanics regulates therapeutic outcome and long-term survival of breast cancer cells by influencing autophagy. SIGNIFICANCE: These findings characterize the persistence of dormant cells at metastatic sites, where soft microenvironments downregulate estrogen receptor expression and upregulate autophagy, thereby promoting therapy resistance in breast cancer cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/19/4103/F1.large.jpg.

Tissue mechanics regulates form, function, and dysfunction.

Morphogenesis encompasses the developmental processes that reorganize groups of cells into functional tissues and organs. The spatiotemporal patterning of individual cell behaviors is influenced by how cells perceive and respond to mechanical forces, and determines final tissue architecture. Here, we review recent work examining the physical mechanisms of tissue morphogenesis in vertebrate and invertebrate models, discuss how epithelial cells employ contractility to induce global changes that lead to tissue folding, and describe how tissue form itself regulates cell behavior. We then highlight novel tools to recapitulate these processes in engineered tissues.

A Soft Microenvironment Protects from Failure of Midbody Abscission and Multinucleation Downstream of the EMT-Promoting Transcription Factor Snail.

Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here, we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or TGFß, known inducers of epithelial-mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression.Significance: These findings reveal tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. Cancer Res; 78(9); 2277-89. ©2018 AACR.