Recapitulating tumor extracellular matrix alignment to decipher its role in eliciting malignant cell phenotypes using a peptide liquid crystal hydrogel

Abstract

The aligned microarchitecture of extracellular matrix (ECM) has been recognized as a significant and novel hallmark of certain tumors, which is gradually uncovered to relate to their malignant progression. However, most artificial scaffolds are isotropic and fail to mimic such aligned organization of tumor-associated ECMs. To address this limitation, we developed a self-assembling peptide-based liquid crystal (LC) hydrogel model to recapitulate the aligned topology of tumor ECM, thereby establishing a platform to investigate the relationship between ECM alignment and malignant cell phenotype. The screened peptide self-assembled into aligned nanofibers via a thermal pathway, forming an LC hydrogel with engineered biological properties. When cultured within the peptide LC hydrogel, tumor cells displayed enhanced proliferation, migration, invasion, and drug-resistance, underscoring the critical role of ECM alignment in promoting aggressive phenotypes. Leveraging the LC hydrogel model, we provided initial insights into the mechanisms underlying malignant progression via Western blot, reverse transcription-quantitative PCR and RNA sequencing analyses. Moreover, by implanting LC hydrogel precultured cancer cells into C57BL/6 mice, we established a tumor model exhibiting accelerated growth. Our findings demonstrate that the self-assembled peptide LC hydrogel can recapitulate tumor ECM alignment and enable the development of rapidly progressing tumor models for cancer research and drug screening.