There is a tiny world inside a tumor, says molecular biologist Shawn Lupold, Ph.D., the Catherine and Iola and J. Smith Michael Distinguished Professor of Urology. It’s like a bustling neighborhood, with buildings, roads, utilities, businesses, and residents.

The microenvironment is made up of much more than just cancer cells, he explains. “It contains blood vessels that deliver nutrients, immune cells designed to fend off disease, supportive tissue cells, and a complex network of chemical signals that allow these cells to communicate with one another. Understanding this neighborhood is crucial because it can heavily influence the behavior of the tumor itself.”

In fascinating work, Lupold, along with pathologist Angelo M. De Marzo, M.D., Ph.D., and oncology research scientist Vasan Yegnasubramanian, M.D., Ph.D., have begun to uncover the significant role of a small but powerful molecule known as microRNA-21 (miR-21) within this dynamic environment. This study represents the first comprehensive analysis of any microRNA’s impact on all the different cell types that make up this tiny neighborhood.

“Cancer cells are incredibly manipulative,” says Lupold. “They don’t operate in isolation. Instead, they actively reshuffle the components of their environment — similar to a corrupt business that gradually takes over and transforms an entire neighborhood to serve its own needs.” One of the key backroom players in this process may be miR-21 – known to be elevated in various cancers, including prostate cancer.

In this study, the investigators used a specialized mouse model that closely mimics the aggressive nature of human prostate tumors. “We found that miR-21 becomes highly active in the surrounding support cells during crucial moments when prostate cancer begins to invade surrounding tissues.”

By “knocking out” the miR-21 gene in this model and employing advanced techniques including single-cell RNA sequencing, the team discovered that the absence of miR-21 significantly slowed cancer progression. “Mice lacking miR-21 exhibited smaller tumors compared to their counterparts with normal miR-21 levels,” says De Marzo. “This finding underscores how miR-21 helps the cancer cells thrive not only by influencing their growth, but also by altering the behavior of surrounding cells.”

Restraining the immune system

One particularly striking revelation was how miR-21 influences the immune landscape within the tumors. Before the body can fight off cancer, its immune cells must recognize the presence of an enemy. “Our findings suggest that miR-21 may help create an environment that allows tumors to evade immune detection, which could facilitate unchecked growth,” says Lupold.

Additionally, the team found that miR-21 influences the signaling pathways in the stroma, the supportive tissue that forms part of the tumor’s neighborhood. “By adjusting these pathways, miR-21 helps create a nurturing environment for cancer growth,” says Yegnasubramanian.

Understanding the intricate and multifaceted ways miR-21 and other microRNAs interact with various cell types within the tumor micro-environment “opens doors to potential new therapies that target not just the cancer cells, but also the surrounding support system,” says Lupold. “This study represents a promising step toward harnessing the power of microRNAs to improve cancer care.”

Other scientists who participated in this study include Kenji Zennami, Mindy Graham, Shireen Chikara, Polina Sysa-Shah, Fatima Rafiqi, Rulin Wang, Bulouere Abel, Qizhi Zeng, Timothy Krueger, Nate Brennen, Sudipto Ganguly, Jelani Zarif, Brian Simons, Ted DeWeese, and Fernanda Caramella Pereira.