Breast cancer cell invasion is influenced by growth factor concentration gradients in the tumor microenvironment. However, studying the influence of growth factor gradients on breast cancer cell invasion is challenging due to both the complexities of in vivo models and the difficulties in recapitulating the tumor microenvironment with defined gradients using in vitro models. A defined hyaluronic acid (HA)-based hydrogel crosslinked with matrix metalloproteinase (MMP) cleavable peptides and modified with multiphoton labile nitrodibenzofuran (NDBF) was synthesized to photochemically immobilize epidermal growth factor (EGF) gradients. We demonstrate that EGF gradients can differentially influence breast cancer cell invasion and drug response in cell lines with different EGF receptor (EGFR) expression levels. Photopatterned EGF gradients increase the invasion of moderate EGFR expressing MDA-MB-231 cells, reduce invasion of high EGFR expressing MDA-MB-468 cells, and have no effect on invasion of low EGFR-expressing MCF-7 cells. We evaluate MDA-MB-231 and MDA-MB-468 cell response to the clinically tested EGFR inhibitor, cetuximab. Interestingly, the cellular response to cetuximab is completely different on the EGF gradient hydrogels: cetuximab decreases MDA-MB-231 cell invasion but increases MDA-MB-468 cell invasion and cell number, thus demonstrating the importance of including cell-microenvironment interactions when evaluating drug targets.

乳腺癌细胞的侵袭受肿瘤微环境中生长因子浓度梯度的影响。然而，由于体内模型的复杂性以及使用体外模型以定义的梯度概括肿瘤微环境的难度，研究生长因子梯度对乳腺癌细胞侵袭的影响具有挑战性。合成了定义的透明质酸（HA）基水凝胶，该凝胶与基质金属蛋白酶（MMP）可裂解肽交联并经多光子不稳定的硝基二苯并呋喃（NDBF）修饰以光化学固定表皮生长因子（EGF）渐变。我们证明，EGF梯度可以差异地影响乳腺癌细胞的侵袭和具有不同EGF受体（EGFR）表达水平的细胞系中的药物反应。光图案化的EGF梯度增加中度表达EGFR的MDA-MB-231细胞的侵袭，减少高表达EGFR的MDA-MB-468的侵袭 细胞，并且对低表达EGFR的MCF-7细胞的侵袭没有影响。我们评估了MDA-MB-231和MDA-MB-468细胞对临床测试的EGFR抑制剂西妥昔单抗的反应。有趣的是，在EGF梯度水凝胶上，细胞对西妥昔单抗的反应完全不同：西妥昔单抗减少MDA-MB-231细胞的侵袭，但增加MDA-MB-468细胞的侵袭和细胞数量，因此证明了评估细胞微环境相互作用时的重要性药物目标。