Matrix Rigidity Influences Breast Cancer Cell Behavior at Bone Marrow-Like Microenvironments
Northcutt, Logan
0000-0003-0830-3965
:
2024-07-17
Abstract
Metastases of breast cancer is a prevalent problem with common sites including the brain, lymph nodes, liver, lung and bone. In the bone microenvironment, metastatic breast cancer cells can form osteolytic lesions and affect the integrity of the bone, causing pathological fractures and impairing patient quality of life. Although signaling mechanisms of osteolysis have been evaluated, little is known about how the mechanical cues of the bone marrow promotes tumor cell growth and invasion. Several models show that the physical forces of the primary microenvironment influence breast cancer cell invasion, but the mechanical cues of the bone microenvironment remain a gap in knowledge. In this project, we utilized model systems to evaluate how matrix rigidities mimicking the bone marrow may contribute to tumor cell invasion and proliferation.
We first sought to create a system to mimic the rigidity of the bone marrow (0.5 kPa – 40 kPa) by using an alginate-Matrigel based hydrogel. We fabricated alginate-Matrigel hydrogels with varying calcium sulfate concentrations to tune the rigidity, and we demonstrated that these hydrogels recapitulated the mechanical properties observed in the bone marrow microenvironment (0.7 kPa to 16 kPa). We encapsulated multiple breast cancer cell lines into these hydrogels to assess growth and invasion. Tumor cells in stiffer hydrogels exhibited modest changes in proliferation and enhanced elongation compared to lower stiffness hydrogels, which suggests that stiffer environments mimicking bone marrow promote invasion.
We then investigated the effects of bone-marrow like stiffnesses on estrogen receptor positive breast cancer. We explored the transcriptional changes that occur at different matrix rigidities associated with the bone microenvironment (bone marrow: 0.5 kPa to 32 kPa; cortical and trabecular bone – 2 x 107 kPa). We observed that lower stiffnesses of the bone marrow contributed to increased gene signatures associated with interleukin signaling. Additionally, downstream estrogen signaling outputs were modified but the estrogen receptor expression remained the same across rigidities. These findings give us insights on what may be changing when ER+ tumor cells encounter rigidities associated with the bone microenvironment.