A recent study has produced intricate 3D models of the internal structures found in various tumor types. These cancer maps illustrate the arrangement of distinct tumor cells and the surrounding cells and how this arrangement shifts when a tumor metastasizes to other organs. According to the researchers, these comprehensive insights may provide scientists with critical frameworks for understanding tumors, potentially leading to innovative treatment methods and ushering in a new chapter in cancer biology.
Led by researchers from Washington University School of Medicine in St. Louis, a new study has created detailed 3D representations of the internal structures of different tumor types. These cancer atlases illustrate how various tumor cells and the cells in their environment are organized in three dimensions and how that organization alters when a tumor spreads to different organs.
The findings offer essential templates about tumors that could help in developing new therapeutic strategies and initiate a transformative period in cancer biology, according to the study’s authors.
This research is part of a collection of 12 papers published on October 30 in the Nature suite of journals by contributors to the Human Tumor Atlas Network, a research consortium supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH). The 3D analysis, featured in Nature, includes extensive data concerning breast, colorectal, pancreas, kidney, uterine, and bile duct cancers.
Over the last decade, there have been remarkable improvements in understanding the roles of cells in a tumor’s microenvironment, including both cancer cells and the supportive cells at an individual cell level. This new research does not only reveal the functions of each cell but also their specific locations within the intact tumor and how they interact with adjacent cells, regardless of whether those cells are close by or further away.
This new data could assist researchers in comprehending how tumors metastasize or develop resistance to treatments, among other critical research areas.
“These 3D maps of tumors are significant because they allow us to visualize what we could only infer about tumor structures and their complexities before,” stated co-senior author Li Ding, PhD, the David English Smith Professor of Medicine. “We previously understood that cancer, immune, and structural cells all coexist in the tumor, often defending the cancer against chemotherapy and immune responses. Now, we can visually delineate those dynamics. We can observe how different regions of the tumor vary in their 3D arrangement and how their behavior shifts in reaction to treatment or when the tumor metastasizes. This research has opened a new frontier in cancer study, with the potential to redefine how we understand and manage cancer moving forward.”
The study is led by Ding, who is also associated with Siteman Cancer Center located at Barnes-Jewish Hospital and WashU Medicine, along with her co-senior authors Feng Chen, PhD, a professor of medicine; Ryan C. Fields, MD, the Kim and Tim Eberlein Distinguished Professor; William E. Gillanders, MD, a professor of surgery, all from WashU Medicine; and Benjamin J. Raphael, PhD, from Princeton University.
3D Tumor Neighborhood Organization
In general, the researchers observed that tumors exhibit greater metabolic activity—meaning they consume more energy—at their centers, with increased immune activity at the edges. They also discovered that a tumor can contain various regions, each characterized by different genetic mutations that drive its growth. These regions are crucial for understanding how they respond to or resist treatment across various cancer types, suggesting that tailored therapies may be necessary to target specific mutations in different areas.
“This understanding of 3D cancer metabolism will influence the efficacy of our current treatments, and in some cases their ineffectiveness, and will promote the development of new therapies in oncology,” noted Fields, who also treats patients at Siteman. “It’s truly groundbreaking.”
Moreover, some regions within tumors exhibit significant immune cell activity, known as ‘hot’ regions, while other areas may be classified as ‘cold’ due to minimal immune presence. Typically, hot regions respond well to immunotherapy, whereas cold regions do not, potentially elucidating why some tumors initially respond to immunotherapies but later show resistance. Identifying different mutation profiles along with cold and hot areas could enable the design of treatment strategies effective against all regions of a single tumor.
The research team, including co-first authors Chia-Kuei (Simon) Mo and Jingxian (Clara) Liu, both graduate students in Ding’s lab, also observed considerable variation in immune cell infiltration across tumors and the locations of different immune cell types like T cells and macrophages. Certain metastatic tumor samples revealed instances of cancer outpacing immune cell defenses, reinforcing the concept of immune cell exhaustion, where an aggressive cancer overwhelms the immune response, thwarting its ability to control tumor growth.
“If we can identify exhausted T cells within a tumor, we may activate them with a checkpoint inhibitor or other immunotherapies,” Ding explained. “However, if they aren’t detected, we can rule out the effectiveness of some immunotherapies. These tumor maps enable us to forecast treatment resistance. We have never had the capability to analyze tumors in this manner before — recognizing the presence of immune cells within the tumor could highlight potential avenues for therapeutic intervention.”
The WashU Medicine researchers also contributed to two additional studies as part of this publication series. One, featured in Nature Cancer and co-led by Ding and Gillanders, provides an in-depth examination of breast cancer, detailing how various breast tumors can originate from distinct cell types. The research uncovered that T cell exhaustion is prevalent in aggressive triple-negative breast cancer. Understanding the “cell of origin” and the immune landscape within breast cancer could inform future therapeutic directions.
The second paper, published in Nature Methods and co-led by Ding from WashU Medicine and Raphael from Princeton, introduces novel methods for conducting 3D analyses of tumors, including those investigated in the study encompassing the six tumor types discussed in Nature.
