Metastasis, the process by which cancer cells leave the primary tumor and establish new tumors in a distant site (or sites) of the body, is perhaps the most terrifying diagnosis faced by cancer patients. Although tremendous progress has been made in recent years in treating primary cancer, traditional therapies such as surgery, radiation, and chemotherapy are rarely effective for metastatic cancer, and, as a result, metastasis is the cause of over 90% of cancer-related deaths. This extraordinary unmet medical need, in combination with the scientific complexity of metastatic cancer, has led The Mark Foundation to partner with researchers tackling this problem through a variety of innovative approaches.
The complexity of metastasis is rooted in the multi-step process that involves an intimate interplay between cancer cells and many different cell types and systems of the patient’s body. For a new tumor to be established at a distant site, the cancer cells must first invade the normal tissue surrounding the primary tumor and then penetrate the wall of a nearby blood vessel to enter the circulation, a process known as intravasation. The cancer cell must then survive the hostile environment of blood, where it encounters shear forces and other physical stresses from the moving fluid, as well as immune cells programmed to kill invaders. The cancer cell then latches onto a vessel wall and extravasates, reversing the process of vessel wall penetration to take root in a new tissue. The final step of the metastatic process is colonization, in which the cancer cell adapts to and proliferates in the new tissue, often an unfamiliar microenvironment in which the bath of nutrients, growth factors, and physical signals from neighboring cells are all very different from the environment where the original tumor flourished.
The last step of colonization, in which a single cancer cell or small clump of cells from the original tumor grows into an overt metastasis, is so challenging that there is often a pause lasting months or even years between the original seeding of the cell and its outgrowth into a metastatic lesion. This fallow period is known as dormancy, and the dormant period explains why certain cancers may recur at distant sites many years after the original tumor has been removed through surgery. The Mark Foundation has awarded ASPIRE grants to two researchers who are studying the phenomenon of dormancy and re-awakening in an attempt to prevent these devastating late recurrences.
Dr. Alana Welm of the Huntsman Cancer Institute at the University of Utah recognized that one of the primary obstacles to eliminating dormant cancer cells is that we don’t know much about them: where they sit in the body, how many there are, what they look like, how they evade detection by the immune system, and what keeps them in a dormant state. Dormant cancer cells are particularly difficult to study because they are a needle in a haystack – too small to be seen by conventional imaging scans, surrounded by vast seas of normal cells in a patient who appears healthy. Dr. Welm has worked closely with a team of breast cancer patient advocates to develop a rapid autopsy program, in which women with a terminal diagnosis of metastatic breast cancer volunteer to donate tissue soon after death. The selfless contributions of these women enable Dr. Welm and her team to apply cutting-edge technologies in single-cell analysis, imaging, and animal modeling to identify and characterize dormant cancer cells, along with their corresponding primary tumors and metastatic lesions, in the context of the surrounding normal tissue. These studies will lay the foundation for new strategies to prevent and treat breast cancer recurrence.
In a complementary approach to understanding cancer cell dormancy, Dr. Julio Aguirre-Ghiso at the Icahn School of Medicine at Mount Sinai is investigating how cancer cells that leave the primary tumor early in the course of the disease can reshape the microenvironment in the distant site where they land, preparing a niche to better support the outgrowth of more aggressive tumor cells that arrive later on. These challenging experiments are enabled by a barcoding technology developed by the Aguirre-Ghiso lab that permits the precise tracking of early- and late-stage tumor cells in mouse models of breast cancer. Dr. Aguirre-Ghiso, who currently serves as president of the Metastasis Research Society, is moving the field towards a nuanced understanding of metastasis with important implications for the timing of preventative and curative interventions.
Dormancy, however, is but one step of the metastatic process. The metastatic cascade is so complex that understanding it holistically is a challenge best suited for team science. In 2020, The Mark Foundation initiated the Endeavor Award program with the goal of uniting scientists across diverse areas of expertise to address urgent questions in cancer research. A multidisciplinary team of investigators from the University of California San Francisco (UCSF) received one of the inaugural Endeavor Awards from The Mark Foundation to understand, prevent, and treat metastasis.
“Metastasis is a really challenging problem; it’s what kills most cancer patients,” says Jeroen Roose, PhD, an investigator in UCSF’s Helen Diller Family Comprehensive Cancer Center (HDFCC), Co-Founder of ImmunoX, and one of the members of the UCSF Endeavor team. “To understand metastasis, you need to study it from many different angles, because it has to do with intrinsic features of a tumor as well as with the larger environment.”
“A lot of therapies have reasonable efficacy for curing and treating primary tumors, but they work much less well when it comes to treating disseminated disease,” says Valerie Weaver, PhD, Director of the Center for Bioengineering and Tissue Regeneration at HDFCC and
another member of the UCSF Endeavor team. “We want to shed light on metastatic disease and come up with new therapies that can target it and prevent it, while also increasing the efficacy of traditional therapies.”
The secret weapon of the UCSF team is a biobank of organoids created from both metastatic lesions and the original primary tumors, derived from patient biopsies and surgical samples. These organoids, which are miniature organ-like clusters of cells grown in lab in a way that mimics the natural environment of the body, will serve as a model system to enable previously unprecedented studies of metastasis. The team is using a multi-omic approach to characterize the metastatic organoids and probe the interactions of metastatic cancer cells with the nervous system and the surrounding extracellular matrix. A long-term goal of the project is to develop preclinical trial models that incorporate different aspects of metastatic fitness, to work toward developing therapies that specifically target metastases.
“At a time when funding becomes difficult and competition becomes fierce, many people contract and build their own little empires,” Dr. Weaver says. “Because of The Mark Foundation’s willingness to go with something that looks at the bigger picture, we are able to build a community. The sky is the limit of what’s possible when you have this kind of group.” The other members of the UCSF Endeavor team are Andrei Goga, MD, PhD, of the Department of Cell and Tissue Biology and Department of Medicine at UCSF, Eric Collisson, MD, Department of Medicine, Division of Hematology/Oncology; Jay Debnath, MD, PhD, Department of Pathology; and Sarah Knox, PhD, Department of Cell and Tissue Biology.
Metastasis is an incredibly complex challenge, and developing therapies to improve the prognosis of patients diagnosed with metastatic cancer will require a deep understanding of the interactions between tumor cells and surrounding normal tissue at each step of the metastatic cascade. The interdisciplinary collaborations, novel technologies, and innovative approaches of these Mark Foundation researchers offer desperately needed hope for patients and their caregivers and loved ones.