KLF4 dependent smooth muscle cell plasticity promotes metastasis

FARE Award Winner

Authors

• M Murgai
• AJ Giles
• C Reid
• M Kasai
• RN Kaplan

Abstract

Metastasis is the major cause of cancer death, for which novel targeted therapies could improve survival. In addition to their impact on the local microenvironment, tumors elicit changes at distant sites that promote metastasis, including stromal cell activation and bone marrow derived cell (BMDC) recruitment. PDGFRa+ stromal cell expansion in pre-metastatic sites is associated with increased extracellular matrix (ECM) that recruits BMDCs. One candidate stromal cell population is vascular smooth muscle cells (SMCs) and pericytes. SMCs/pericytes exhibit remarkable plasticity when they switch from a contractile to an activated, inflammatory phenotype characterized by increased proliferation, migration and ECM remodeling. SMC activation is KLF4-dependent and can be miR143/145-regulated in development and disease. Although SMC plasticity plays crucial roles in many disease states, whether SMC plasticity occurs in metastatic microenvironments is unknown. We hypothesized that KLF4-mediated SMC/pericyte plasticity contributes to metastasis-promoting microenvironments. We found that SMCs are activated in pre-metastatic tissues, where they proliferate and become KLF4+PDGFRa+ in tumor-bearing mice and non-tumor-bearing mice treated with tumor-conditioned media (TCM). SMCs treated with TCM in vitro are also activated, and secrete ECM that enhances tumor cell adhesion, proliferation, and migration. Disrupting KLF4-dependent SMC activation decreases metastasis in an SMC-specific, inducible KLF4 knock-down murine model. Circulating miR143/145 is elevated in pre-metastatic tumor-bearing mice and metastatic patients. shRNA-mediated disruption of tumor-derived miR143/145 delays metastasis and improves survival. We demonstrate that KLF4- and miR143/145-dependent SMC plasticity promotes metastasis in part by altering ECM at pre-metastatic sites. SMCs/pericytes represent a novel and previously unappreciated stromal cell target in metastasis.

Scientific Focus Area: Cancer Biology

This page was last updated on Friday, March 26, 2021