New research from the Medical University of Vienna in collaboration with Stanford University and the University of California, San Francisco, gives unprecedented insights into the dynamic remodeling of immune cells in the metastatic niche starting from early tumor development up to late-stage metastasis. The study was recently published in Cancer Cell.
Metastasis, the spread of tumor cells to different organs, is detrimental for cancer patients due to the lack of effective therapies specifically targeting metastatic disease. During the process of metastasis, the tissue of the metastatic site gets remodeled to host disseminated tumor cells. The development of these metastatic niches is believed to play an important role in supporting tumor cell outgrowth into overt metastasis. However, despite its devastating impact on patients’ lives, little is known about these processes and the remodeling of metastatic niches. Interestingly, changes in the tissues of future metastasis already happen during the early stages of tumor progression, even before disseminated tumor cells are present. Studying these pre-metastatic niches could yield promise to develop therapies to prevent metastasis from occurring.
Single-Cell RNA-sequencing and bioinformatic tools
To systemically study immune remodeling in metastatic niches the research team led by Juliane Winkler (Center for Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna) and Ansuman Satpathy (Stanford University, Gladstone-UCSF, Parker Institute for Cancer Immunotherapy) longitudinally profiled immune cells in lung tissue of two commonly used breast cancer mouse models at single-cell resolution. By employing a single-cell RNA-sequencing method previously developed by first author Christopher McGinnis together with Juliane Winkler at the University of California, San Francisco (MULTI-Seq McGinnis et al 2019, Nature Methods) they were able to profile metastatic niches with a fine-grained longitudinal sampling resulting in more than 70 samples from two different breast cancer models. “This is the first time that we have the technologies and bioinformatic tools available to describe the dynamic changes of tens of thousands of cells across the different stages of metastatic progression with unprecedented detail.” says first author Chris McGinnis.
Blocking the immunosuppressive pre-metastatic niche might prevent metastasis
The study discovered that different immune cells in the pre-metastatic niche are remodeled in a similar way: tissue-resident myeloid cells, such as interstitial and alveolar macrophages but also recruited myeloid cells upregulate inflammatory gene programs that are associated with immunosuppression. This pan-myeloid remodeling may play a crucial role in the early development of an immunosuppressive environment in the distant tissues, where disseminated tumor cells can evade T-cell-mediated killing, as immunosuppressive regulatory T-cells were also found to further increase with metastatic progression. “Our findings have the potential to inspire the first generation of anti-metastatic immuno-therapies. Blocking these immunosuppressive remodeling processes early during metastatic niche development at the time of primary tumor diagnosis we might be able to prevent metastasis that usually occurs many years later. “ says Juliane Winkler.
In future studies, the research team of Juliane Winkler is interested in how spatially restricted niches influence metastatic progression.
“We are trying to gather as much data as possible about the dynamic process of metastasis to identify loopholes that can be exploited therapeutically.”
Source – Medical University of Vienna
McGinnis CS, Miao Z, Superville D, Yao W, Goga A, Reticker-Flynn NE, Winkler J, Satpathy AT. (2024) The temporal progression of lung immune remodeling during breast cancer metastasis. Cancer Cell 42(6):1018-1031.e6. [abstract]