Precancer Atlases Might Intercept Malignancies

Improvements in technology have been facilitating efforts to prevent cancer. The creation of a precancer atlas will be a critical step, researchers say.

A precancer atlas creates “a map of all the cellular and molecular changes in a precancerous lesion,” explains Avrum Spira, MD, MSc, of Johnson & Johnson and Boston Medical Center in Massachusetts, who discussed the concept at the American Association for Cancer Research Annual Meeting 2022 in New Orleans, LA, held April 8–13. The atlas can show “molecular changes [in] all the cells in that lesion” and “how those changes evolve over time as the lesion either progresses to or regresses away from cancer.”

Compiling spatial and genomic information into a map helps assign identities to single cells within these lesions, provides insight into how the microenvironment is organized, and shows how this organization could impact cancer development. Although “atlases are not hypothesis testing, they generate hypotheses,” Spira said.

Spira and his team investigated the immune microenvironment in the early development of squamous lung cancer. Through a pilot precancer atlas, they found that in premalignant lesions with a lower chance of developing into invasive cancer, “there's a much higher number of immune cells, specifically CD8⁺ T cells,” Spira said. This “suggests the immune microenvironment may be a determinant of premalignant lung [cancer] progression.”

The team subsequently performed miRNA sequencing “to see which miRNAs specifically acted on immune genes,” says Jennifer Beane, PhD, of Boston University. An analysis by bioinformatics graduate student Boting Ning suggests that miRNA-149-5p is overexpressed in progressive premalignant lesions and downregulates NLRC5. “By suppressing NLRC5, MHC1 genes are suppressed and CD8⁺ T cells are not recruited to the epithelium,” explains Beane. The anticorrelation between miRNA-149-5p and NLRC5 is thought to eliminate antigen presentation to immune cells, allowing oncogenic mutations to go unnoticed. Researchers are investigating this hypothesis in preclinical models.

Spira and his colleagues are not the only group using a precancer atlas to evaluate disease development. Researchers at Dana-Farber Cancer Institute, Harvard Medical School (HMS), and Brigham and Women's Hospital, all in Boston, explored the use of an early-stage precancer atlas to examine immune system shifts in premalignant melanoma lesions.

Although further investigation is needed to corroborate the findings, the team hypothesizes that some melanoma immunosuppressive mechanisms consist of immune cell types acting on one another rather than cancer cells. “We think it's macrophages and dendritic cells suppressing T cells, not tumor cells suppressing T cells,” says Peter Sorger, PhD, of HMS. In other words, it's estimated that the “tumor can attract macrophages and put them into a state where they're immunosuppressive.”

A precancer atlas “can visually discriminate where the immune system is having success and where it's failing,” adds Sandro Santagata, MD, PhD, of Brigham and Women's. The team is using the maps of early-stage melanoma to find mechanisms that support successful immune responses, which they “hope to translate into better treatments for patients.”

Both research initiatives show the potential of a precancer atlas in developing hypotheses about precancerous lesions and their microenvironments, but the tool's routine use isn't around the corner. “The Cancer Genome Atlas took more than a decade from inception before we saw it benefiting patients,” Spira said. “We're at the beginning of the precancer atlas journey.” –Natalie DiDomenico

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.