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The Mechanical Underpinnings of Breast Cancer

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I am Prateek S. Katti and my life goal is to make a significant contribution to the improvement of human health. I just graduated summa cum laude with Chemical Engineering and Biochemistry & Molecular Biology majors at the University of Massachusetts -- Amherst. For my honor's thesis, I investigated the mechanical underpinnings of breast cancer metastasis with the guidance of faculty and graduate students.

An interdisciplinary research effort spearheaded by Professor Alfred Crosby and Shelly Peyton of the University of Massachusetts -- Amherst bridges together cutting-edge work from the fields of Polymer Science, Chemical Engineering, and Biochemistry to generate a novel method to recapitulate the metastatic breast cancer tumor microenvironment in order to elucidate the role of mechanical cues present: stiffness and topography. This work is generously funded by the Materials Research Science and Engineering Center (MRSEC), which aims to "support, promote, and produce state-of-the-art research and education in polymer materials." Breast cancer is one of the most common non-skin cancers, and is the second leading cause of cancer-related deaths of U.S. women. Although the overall breast cancer death rate has dropped steadily since 2000 due to improvements in early detection and treatment, statistics compiled by the American Cancer Society estimate that there have been 57,650 in situ cases, 230,480 invasive cases and 39,520 deaths in 2011. In situ cases, where cancerous cells remain confined locally in the ducts, are of minimal danger as long as they are diagnosed and treated. Breast cancer metastasis, i.e. the invasion of cancerous cells to the lymph nodes or other locations outside the breast, is the primary mechanism by which breast cancer becomes lethal. The survival rate for women diagnosed with localized breast cancer is 98 percent (American Cancer Society, 2012). Identification of what underlies breast cancer metastasis is clearly relevant to finding solutions to this public health concern.

Traditionally, breast cancer research has been focused on gene expression changes occurring in tumor cells, and how these genetic alterations lead to metastasis. However, over the past two decades a consensus has gathered that intrinsic changes in the cell's mechanical and topographical microenvironment may also drive progression. We now know that breast cancer metastasis is associated with dynamic reorganization of the tumor microenvironment, the tissue's extracellular matrix (ECM). The ECM of healthy breast tissue is a dense, sheet-like mesh of randomly packed fibrillar glycoproteins, proteoglycans, and collagen fibers organized parallel to the epithelial-stromal interface. However during metastasis, protein bundles are re-oriented perpendicular to the tumor boundary. These topographic ECM changes are thought to facilitate cell movement out of the tumor. In addition to topographic changes, breast cancer metastasis is marked by stiffness changes. The ECM becomes denser, owing to increases in collagen mass as well.

These dynamic structural changes of the tumor microenvironment play a pivotal role in breast cancer metastasis. Here we describe a method to recapitulate the metastatic tumor microenvironment such that we may parse the roles of stiffness and topography during breast cancer metastasis. We pattern cell-adhesive, micron-spaced, quantum-dot (QD) lines onto soft hydrogel surfaces, seed them with breast cancer cells, and analyze cell response over a 12-hour time period via green florescence protein (GFP) cell tracking. We set out to observe how cell behavior changes according to changes in substrate patterning. We use poly(ethylene glycol) (PEG) based hydrogels because their moduli are easily controlled. In specific, we use PEG- phosphorylcholine (PC) hydrogels in order to block protein adsorption and prevent cell adhesion to un-patterned gel surfaces. Cadmium selenide (CdSe) QDs containing biocompatible-polystyrene ligands were generously synthesized by Professor Todd Emrick's research group, in the Polymer Science & Engineering Department at UMass. We pattern lines by ultraviolet (UV) crosslinking QDs assembled into lines by stick-slip patterning. Stick-slip patterning permits tunable control of line spacing and width over a wide range of substrates -- our model allows us to explore cell response to an array of stiffness, topographies, and bulk moduli. Preliminary data shows promising results; we observe that cells adhere to our patterned substrates and some appear to be influenced by the lines. We have found cells that migrate along the lines, turn and move perpendicular to patterning, and re-turn to traverse along lines again. We look to refine and optimize our approach as we continue to explore this interesting system.

This work was made possible by guidance and support from graduate candidates Yujie Liu of Polymer Science & Engineering and Danielle Ryman of Molecular & Cellular Biology at UMass Amherst. This collaborative, interdisciplinary research directed by Professor Alfred J. Crosby and Professor Shelly Peyton of the University of Massachusetts Amherst, bridges together the fields of Polymer Science and Engineering, Chemical Engineering, and Molecular & Cellular Biology. We gratefully acknowledge the generous funding provided by the National Science Foundation Materials Research Science and Engineering Center (MRSEC).