Ryan Carpenter – Jungwoo Lee Lab
Implantable humanized pre-metastatic niches capture microenvironmental regulation of disseminated tumor cells
Metastatic relapse in secondary organs is the leading cause of cancer related death. Many cancer survivors carry disseminated tumor cells (DTCs) but do not experience relapse because their DTCs remain in a dormant state or have not transitioned to an aggressive phenotype within the patient’s lifetime. Accumulating data suggests that the post-dissemination phase of cancer biology is regulated by intrinsic genetic instability of DTCs and their bi-directional interaction with the surrounding microenvironment. Understanding how the local milieu prevents or aids the transition to an aggressive phenotype represents an opportunity to develop therapeutic strategies to prevent or delay lethal metastasis. Although mouse models have served as an enabling tool for studying human cancer biology, they are essentially limited. The opportunity to study rare dormant DTCs is restricted by difficulties in detection and the simultaneous formation of active tumors which greatly reduce the host’s lifespan. Here we introduce a new approach to study metastatic cancer cells using implantable microenvironments that can isolate a population of dormant DTCs to capture their phenotypic transition in a human relevant setting. Microfabricated porous scaffolds composed of non-degradable synthetic hydrogel directed a unique foreign body response forming and maintaining key microenvironmental features of the pre-metastatic niche including (i) dense vasculature, (ii) bone marrow derived cells, and (iii) increased immune cell activity. The pre-metastatic niche was humanized in a physiologically relevant manner with pre-seeded human bone marrow stromal cells, DTCs derived from an orthotopic xenograft human prostate tumor, and intravenously introduced human peripheral blood mononuclear cells (hPBMCs). An early stage metastatic niche was retrieved from the host mouse and re-implanted into a secondary mouse to separate aggressive primary and secondary tumors and prolong the experimental timeframe. Ten weeks after scaffold transplantation a broad range of metastatic progression from dormant single cells to aggressive metastases were observed. hPBMCs were found to play a suppressive role on secondary tumor growth, yet did not prevent the formation of large colonies. Histological analysis via traditional and whole tissue clearing techniques revealed unique signatures of the dormant and aggressive tumor microenvironments and demonstrate the importance of vasculature and innate immune cells as regulators of tumor awakening. Our work demonstrates the ability of implantable biomaterial driven pre-metastatic niches to study long-term dormancy of DTCs in vivo and has uncovered important factors that drive the transition from stable to aggressive tumors. We envision that implantable pre-metastatic niches will be an enabling tool for studying the dormant microenvironment and aid in the development of drugs to target dormant tumor cells.
Yen Tran – John Klier and Shelly Peyton Lab
Strain-responsive cryptic gels and their applications
Yen H. Tran, John Klier, Shelly R. Peyton
Gels are an increasingly important class of soft materials with applications ranging from regenerative medicine to industrial and consumer product materials. A typical property of gels is their relative mechanical weakness, which further weakens under repeated strain. Mechano-stiffening materials, particularly proteins, are encountered frequently in nature, showing an immediate response to deformation. These polymers inspire the creation of synthetic strain-responsive materials. However, strain-stiffening response cannot be easily duplicated by synthetic materials and to date the synthesis of strain-stiffening materials remains elusive. Here, I aim to create a new class of responsive gels with latent crosslinking moieties that exhibit strain-stiffening behavior. Molecular shielding design elements regulate the strain-sensitivity and spontaneous crosslinking tendencies of the polymer network. These strain-responsive gels represent a rational design of new advanced materials with on-demand stiffening properties with potential applications in elastomers, adhesives, foams, films, and fibers.