Tuning Hydrogel Adhesivity and Degradability to Model the Influence of Premetastatic Niche Matrix Properties on Breast Cancer Dormancy and Reactivation

Abstract

Dormant, disseminated tumor cells (DTCs) can persist for decades in secondary tissues before being reactivated to form tumors. The properties of the premetastatic niche can influence the DTC phenotype. To better understand how matrix properties of premetastatic niches influence DTC behavior, three hydrogel formulations are implemented to model a permissive niche and two nonpermissive niches. Poly(ethylene glycol) (PEG)‐based hydrogels with varying adhesivity ([RGDS]) and degradability ([N‐vinyl pyrrolidinone]) are implemented to mimic a permissive niche with high adhesivity and degradability and two nonpermissive niches, one with moderate adhesivity and degradability and one with no adhesivity and high degradability. The influence of matrix properties on estrogen receptor positive (ER+) breast cancer cells (MCF7s) is determined via a multimetric analysis. MCF7s cultured in the permissive niche adopted a growth state, while those in the nonpermissive niche with reduced adhesivity and degradability underwent tumor mass dormancy. Complete removal of adhesivity while maintaining high degradability induced single cell dormancy. The ability to mimic reactivation of dormant cells through a dynamic increase in [RGDS] is also demonstrated. This platform provides the capability of inducing growth, dormancy, and reactivation of ER+ breast cancer and can be useful in understanding how premetastatic niche properties influence cancer cell fate.

Dormancy-inducing 3D-engineered matrix uncovers mechanosensitive and drug protective FHL2-p21 signaling axis

“…We further explored this stiffness-induced growth arrest state by the well-established ratio of phosphorylated forms P-ERK low :P-p38 high as a dormancy marker ( 3 , 29 , 33 , 37 , 38 ). We analyzed the ratio at a single cell level within 3D stiff and soft alginate hydrogels using immunofluorescence (Supp.Fig.S2e).…”

“…Interestingly, biochemical properties such as integrin binding and matrix metalloproteinase (MMP) degradation profiles can also recapitulate dormancy induction at metastatic sites ( 24 ). Poly(ethylene glycol) hydrogels manipulated with MMP-cleavable crosslinkers and arginine-glycine-aspartic acid (RGD) integrin-binding sites have uncovered mechanisms underlying dormancy induction and reactivation of BCCs ( 22 , 29 , 30 ). As for other biochemical properties, such as nutrient deprivation in growth arrested cells, serum starvation has been used to explore the reorganization of fibronectin secreted by dormant cells ( 31 ).…”