Abstract 2090: Designer microenvironments to control oncogenic phenotype

“Half of the secret of the cell lies outside the cell (Mina Bissell)”. This key aspect, over the genetic influence on cancer, has been largely neglected in the context of oncology drug discovery. In fact, the impressive reciprocity between extracellular matrix (ECM) components and cells, is responsible for numerous biological processes from homeostasis to disease development and progression. For example, alterations of cell-ECM interactions were shown to phenotypically revert cancer to healthy cells and vice versa, regardless of their genetic features. Furthermore, changes in cell adhesion to the ECM were reported to alter cancer cell sensitivity to chemo-therapies, and stiffening of the ECM was observed to favor cancerous cell phenotypes. Here, we present a case to address the question: how do specific modifications of ECM features generate different cell phenotypes. The answer will enable the investigation of ECM-induced drug resistance, disease progression and identification of new drug targets. Today, research with cancer cells and their interactions with the ECM employs natural matrices that provide biologically relevant yet undefined environments that cannot be systematically altered. However, recent advances in biomaterial engineering applied to cell biology have paved the road to overcome these limitations. Here, we use industrially-available QGel matrices, namely synthetic ECM analogues, whose biological, biochemical and structural features can be precisely tuned to systematically test their impact on cell behavior. We have investigated the impact of 60 different ECM combinations on A549 cells, a well differentiated human lung adenocarcinoma cell line with residual characteristic of alveolar type II epithelial cells. The contribution of matrix degradability, stiffness and cell attachment sites derived from several ECM proteins were individually depicted. When A549 were seeded as single cells in the different ECMs, two distinct phenotypes were identified within 4 weeks of culture: (i) full cell spheroid morphology (mass), which is the major phenotype observed in Matrigel, was obtained within MMP-degradable hydrogels; and (ii) acinar morphology (acini) that matured over time from full cell spheroids within non-degradable hydrogels containing specific integrin binding sites. We speculate that the acini phenotype reflects the healthy nature of the alveolar epithelial cells, while the mass morphology has cancerous characteristics. Interestingly, our da