Metastasis remains the biggest hurdle in the fight to lower cancer mortality rates globally, according to Dr. Karuna Ganesh, a gastrointestinal oncologist from Memorial Sloan Kettering Cancer Center (MSK). This process occurs when a primary tumor, like colorectal cancer, spreads to other parts of the body such as the brain, liver, or bones.
Metastasis remains the primary challenge to reducing cancer deaths worldwide, says Memorial Sloan Kettering Cancer Center (MSK) gastrointestinal oncologist Karuna Ganesh, MD, PhD. That’s when a primary tumor — colorectal cancer, for example — spreads to a new part of the body, such as the brain, liver, or bones.
Although the new tumor is still classified as colorectal cancer and not as cancer from the brain, liver, or bones, the cells within this new tumor are significantly different from those in the primary tumor. Understanding these differences is crucial.
Dr. Ganesh emphasizes, “We often say that people don’t die from cancer itself, but from metastasis.” While we have effective methods to treat primary tumors, including surgery and sometimes chemotherapy or radiation, metastatic disease often responds to initial treatments but fails to eliminate all cancer cells. The cancer cells that persist post-treatment tend to become increasingly aggressive, leading to treatment resistance.
Gaining effective treatments for metastasis requires a deeper understanding of the changes cancer cells undergo when they metastasize, as well as the mechanisms that drive these changes.
A recent MSK study published on October 30 in Nature, led by Dr. Ganesh and MSK computational biologist Dana Pe’er, PhD, is shedding light on metastasis and revealing potential new treatment strategies.
Study Illuminates Differences Between Primary and Metastatic Colorectal Cancer
The study presents new insights into how metastatic cancer cells can revert to earlier, more flexible developmental states in a phenomenon known as “cellular plasticity.”
Cellular plasticity refers to cancer cells’ capability to alter their identity; for example, intestinal cells can change to take on completely different characteristics like skin, bone, or neuroendocrine cells.
By analyzing samples from patients with advanced colorectal cancer, researchers discovered distinct patterns in the way metastatic cells reprogram themselves to access these primitive states.
Dr. Pe’er, also a Howard Hughes Medical Institute Investigator, said, “Instead of focusing solely on genetic mutations responsible for initiating cancer, we examined the ability of cancer cells to alter their identity during metastasis.”
This research necessitated innovative methods, high-level experimental and computational skills, and significant collaboration among oncologists, surgeons, and laboratory researchers, facilitated by MSK’s extensive expertise and cooperative environment.
The study was spearheaded by co-first authors Andrew Moorman, MS, a computational biologist, and Tri-Institutional MD/PhD student Elizabeth Benitez, along with postdoctoral fellow Francesco Cambuli, PhD, all from Dr. Ganesh’s lab.
Studying Metastasis Using Three Kinds of Tissue
Researchers collected samples from each of 31 patients, including tissue from their primary tumors, adjacent healthy tissue, and metastatic tumors (commonly from the liver).
They employed single-cell RNA sequencing, advanced immunofluorescence microscopy, and organoids (mini lab-grown model organs) to investigate how cancer cells evolve during metastasis.
The study included both untreated patients and those who had undergone chemotherapy prior to surgery, with some providing additional samples later.
By analyzing matched tissue samples, researchers glean insights into one of cancer’s most significant challenges. Traditional laboratory models like cell lines or mouse models frequently fail to accurately reflect human metastatic processes, with mouse cancers often spreading too quickly compared to human cases.
“Our focus was on advanced cancer in humans, which demands better treatment solutions,” Dr. Ganesh explains. “Collecting samples during surgery on patients with metastatic disease proved challenging, as operations are rarely conducted to remove metastatic tumors.”
Usually, different surgeons handle primary tumors and metastases, complicating the collection of samples across various sites. “We had to foster collaboration to study all these samples during one surgery,” adds Dr. Ganesh. “This approach to simultaneously analyze normal tissue, primary tumor, and metastasis from the same patients offers unprecedented insight.”
Toward a Deeper Understanding of Metastasis
The process of normal cells developing into primary colorectal tumors has been extensively researched. During this phase, tumor cells adopt characteristics akin to intestinal stem cells, initiating their first regression to a more primitive state.
Interestingly, the new study reveals that metastatic colorectal cancer cells do not maintain the features of intestinal stem cells found in their primary tumors. In fact, the more these metastatic cells evolve, the less they resemble their original intestinal cell identities.
A detailed computational analysis identified a consistent pattern: “Despite individual differences in patients’ cancers, the cells from all tumors eventually align with a fetal-like state,” remarks Dr. Pe’er.
This fetal-like state closely resembles the primordial endoderm, the cells that eventually form the intestines during early embryonic development.
From there, metastatic cells can evolve even further back in time, gaining the potential to develop into different cell types, such as skin or nerve cells.
“The signature we identified aligns closely with developmental processes occurring at six weeks gestation,” Dr. Pe’er states. “Specifically, week six, day 6.6.”
Implications for Treating Metastatic Cancer
This ability of cancer cells to ‘time travel’ is a survival tactic, enabling them to withstand various treatments, particularly chemotherapy, highlights Dr. Ganesh.
Throughout patients, metastatic cells tend to revert to the same primitive state, engaging gene programs that allow them to infiltrate various tissues and exhibit stronger resistance to cancer treatments.
“This discovery is critically important from a clinical perspective,” Dr. Ganesh emphasizes. “If these cells need to reach a specific state to rebuild a tumor after therapy, targeting this state becomes a key vulnerability.”
This opens up avenues for targeting both the mechanism that allows entry into this primordial state and the state itself, an area of ongoing research at MSK.
What Organoids Are Teaching MSK Researchers
Organoids derived from matched patient samples are providing unique insights that other methods might not offer.
Dr. Ganesh notes, “We understand that metastatic and primary cancer cells differ, but organoids allow us to explore ‘Why are they different?’ Are they reacting to varying conditions in the liver versus the colon?”
The study revealed that primary tumor cells from the colon cannot survive in the liver environment. Conversely, metastatic cells thrive in both the colon and liver.
“This indicates a higher level of plasticity,” Dr. Ganesh adds. “Our research is the first evidence of the type of plasticity in metastatic cells that facilitates adaptations to varying environmental cues.”
Ultimately, the team is hopeful that these findings could serve as a framework for understanding metastasis better and for addressing cellular plasticity in advanced cancer cases.
