The Tuesday, April 9, plenary session at the American Association for Cancer Research Annual Meeting 2024, Evolution of the Genome, Microenvironment, and Host through Metastasis, tackled key themes that have transformed our understanding of metastasis.

The session is available on demand for registered Annual Meeting attendees through July 10, 2024, on the virtual meeting platform.

Session Chair Cyrus Ghajar, PhD, associate professor at the Fred Hutchinson Cancer Research Center, called attention to the advances in metastasis research since the last time a plenary session focused on this topic at the AACR Annual Meeting, 14 years ago.

“Back then our understanding of metastases was as a linear process with obligate steps,” he said.  

Metastatic progression is now thought of as a multifaceted evolutionary process, driven by concurrent and partially overlapping events, rather than an ordered cascade, Ghajar explained. The plenary speakers explored the complexities of how cancer researchers now view metastasis along with novel ways to target the process.

Changes in the genotype and phenotype of the metastatic seed

Christoph A. Klein, MD, chair of experimental medicine and therapy research at the University of Regensburg in Germany, explored the origins of metastases by tracking the clonal lineages of normal and cancer cells across the continuum of disease, from primary tumorigenesis to the development of metastases.

Klein described how genome-wide microsatellite profiling of disseminated cancer cells (DCCs) and normal cells in the bone marrow, along with primary and metastatic tumor cells, helped researchers develop a phylogenetic tree of the metastatic seed. He said that DCCs that form the metastatic seed were evolving in parallel with the primary tumor and were not merely linear descendants of the primary tumor.

Klein then focused on isolation of these rare DCCs and characterization of their phenotypes. DCCs isolated from patients before the development of overt metastases had a more stem-like embryonic phenotype compared to those from patients with overt metastases, and the presence of DCCs with this phenotype correlated with poor survival outcomes.

Klein described data on potential markers that are expressed specifically on metastatic-seed cells, including the tyrosine kinase c-KIT.

“If we want to target the metastatic seed—for example, in our adjuvant therapy settings—maybe now we have new markers,” he said.

Exploring gene expression and epigenetic plasticity in metastatic progression

Dana Pe’er, PhD, chair of the computational and systems biology program at Memorial Sloan Kettering Cancer Center, focused on the role of gene expression and epigenetic plasticity in enabling DCCs to overcome the multiple hurdles to colonizing a new organ system or site during metastasis.

Pe’er used examples in colorectal cancer (CRC) and pancreatic cancer to illustrate the processes through which tumors transition to form metastases. In tumor cells, both stem-like and differentiated gene expression programs were active. Moreover, gene programs active in tumor cells included expected (canonical) and unexpected (non-canonical) modules—for instance, CRC cells expressed canonical modules involved in epithelial-to-mesenchymal transition as well as non-canonical modules associated with unrelated differentiated lineages such as osteoblasts.

“Metastases have to be targeted differently,” Pe’er said. “If we can understand the barrier, the hurdle, that the tumor is trying to overcome [to colonize a new organ or site], we can directly target this hurdle. We can raise the barrier.”

She added that metastases overcome multiple hurdles and thus, it may be difficult to develop therapies that target multiple barriers. Rather, a better understanding of the plasticity that underpins metastatic progression can help devise ways to target this plasticity itself.

Metabolite signaling may drive aggressive tumor biology

Sarah-Maria Fendt, PhD, professor of oncology at VIB-KU Leuven Center for Cancer Biology and recipient of the 2024 AACR Award for Outstanding Achievement in Basic Cancer Research, focused on metabolic rewiring and its role as a prerequisite of phenotypic plasticity and the subsequent promotion of metastases.

Fendt explored the role of metabolite signaling as a driver of the aggressive biology and treatment resistance characteristic of metastases. She presented data demonstrating that aggressive metastases upregulate protein translation, driven by aberrant activation of the translation initiation factor eIF5A, which in turn may be regulated by the metabolite aspartate.

Fendt said, “I hope I have convinced you today that aspartate, this molecule which is found to be only important for protein, RNA, and DNA synthesis, actually has a signaling role in cancer.”

Systemic effects of metastases

David C. Lyden, MD, PhD, professor of pediatrics in the Division of Hematology and Oncology at Weill Cornell Medical College, introduced the topic of the multiorgan impact of cancer, stating that, “even when you have microscopic cancer, you have a tremendous amount of tumor-secreted factors that get released into the circulation.” He said that these factors may not only drive metastasis but also impact other organ systems.

Lyden said that extracellular vesicles and particles (EVPs), a heterogenous group of vesicle-bound structures, are among the most important tumor-secreted factors that enable long-range communication between tumors and cells at distant sites.

Lyden noted that different cellular components are selectively packaged into EVPs that originate from tumor cells, such that therapies directed at targets in or on tumor cells may not act on EVPs. He added, “Importantly, these EVPs can affect a wide range of systemic effects of cancer, such as cachexia [and] depression.”

Lyden shared data on the role of EVPs in thrombosis, a major cause of death in cancer patients, and liver and metabolic dysfunction. He said that their analyses revealed a potential role for integrins on the surface of EVPs in inducing thrombosis, as well as in determining the organotropism of metastases.

Lyden said that it is critical to start thinking about cancer therapies involving multiple organs.