Bone is a common site for metastasis of solid cancers, but histological and molecular features of bone metastases are not well understood. In a new study published in Cell Genomics, researchers at Baylor College of Medicine and the University of Texas MD Anderson Cancer Center use RNA sequencing to characterize bone metastases from eight cancer types. The findings identify three distinct immune ecosystem archetypes.
"Bone metastases vary widely from person to person, yet all bone metastases are treated similarly with treatment targeting one cell type, osteoclasts. Some patients do not respond to this treatment. In this study, we examined the heterogeneity of bone metastases across different cancer types and within each cancer type," said co-corresponding author Dr. Xiang H.-F. Zhang, director of the Lester and Sue Smith Breast Center and professor of molecular and cellular biology at Baylor.
The Zhang lab worked with Dr. Robert L. Satcher, orthopedic surgeon and associate professor in the Department of Orthopaedic Oncology at MD Anderson, to obtain 42 bone metastases samples from eight different cancer types. "The interesting finding is that there are both similarities and differences that are cancer-type specific. Dr. Zhang's work previously focused on breast cancer bone metastasis, and I focused on renal cell carcinoma bone metastasis. By working together, we were able to approach the problem with a unique combined perspective, which critically informed our research strategy," said Satcher, co-corresponding author of the study.
Researchers conducted RNA sequencing and found the metastases fell into three distinct ecosystem archetypes characterized by enrichment of different immune cells: 1) macrophages and osteoclasts, 2) regulatory and exhausted T cells and 3) monocytes. They validated the archetypes using previously published RNA sequencing data of 158 bone metastases across 10 cancer types.
The team found that archetype does not always coincide with tumor origin. Metastases from the same cancer type often fell into different archetypes, and metastases from different cancer types sometimes fell into the same archetype. These findings indicate both convergent and divergent evolution pathways - cancers originating from different organs can evolve similar immunosuppression and bone colonization mechanisms, and cancers from the same primary organ can develop parallel mechanisms.
The results of this study suggest a need to investigate different treatment strategies for different archetypes. For example, metastases in the exhausted T cell archetype may respond better to interventions that activate those T cells, rather than traditional anti-osteoclast treatment.
"Our analysis identified a large number of potential therapeutic targets within each archetype that can be studied for validation," said first author Fengshuo Liu, graduate student in the Zhang lab. "Our data is all publicly available, and many groups are already using it for other studies."
"This study highlights the power of pan-cancer research. The border of different cancer types becomes blurred when they all come to the same place in the bone, so this is a unique opportunity to study different types in the same microenvironment," said Zhang, William T. Butler, M.D., Endowed Chair for Distinguished Faculty and co-leader of the Breast Cancer Program at the Dan L Duncan Comprehensive Cancer Center at Baylor.
Other authors who contributed to this work include Yunfeng Ding, Zhan Xu, Xiaoxin Hao, Tianhong Pan, George Miles, Siyue Wang, Yi-Hsuan Wu, Jun Liu, Igor L. Bado, Weijie Zhang, Ling Wu, Yang Gao, Liqun Yu, David G. Edwards, Hilda L. Chan, Sergio Aguirre, Michael Warren Dieffenbach, Elina Chen, Yichao Shen, Dane Hoffman, Luis Becerra Dominguez, Charlotte Helena Rivas, Xiang Chen, Hai Wang and Zbigniew Gugala. They are affiliated with one of the following institutions: Baylor College of Medicine, MD Anderson Cancer Center and University of Texas Medical Branch.
This work is supported by the U.S. Department of Defense (W81XWH-21-1-0790, HT9425-23-1-049), National Cancer Institute (CA183878, CA251950, CA277838-01A1, CA271498, U01CA252553) and Breast Cancer Research Foundation. Additional funding comes from the Cancer Prevention and Research Institute of Texas (RP180672, RP200504, RP150578, RP170719) and National Institutes of Health (P30 CA125123, S10 RR024574, S10 OD025251, S10OD025240, DK56338, CA125123, ES030285).
