Columbia Team Tackles Bladder, Esophageal Cancers

Five years ago, cancer researcher Cory Abate-Shen assembled a team of researchers from Columbia and other institutions to tackle some of bladder cancer's biggest unknowns. Compared with other common malignancies, bladder cancer has been relatively understudied, though it's the fifth most common cancer in the U.S., with roughly 85,000 diagnoses each year.

The question at the top of the team's to-do list: Why do some bladder cancers that should have favorable prognoses evolve into more invasive and life-threatening tumors?

What the team discovered-that bladder cancer cells can alter their identities to evade treatments, an example of what is termed lineage plasticity-has changed the team's approach to finding new therapies.

"Biologists used to think that once cells developed into their mature states, they couldn't reverse course or develop into other types of cells," says Abate-Shen, professor of molecular pharmacology and therapeutics at Columbia University Vagelos College of Physicians and Surgeons, who leads the team. "We've recently learned that plasticity is relatively common, and it represents a formidable challenge for treating cancer because it means that malignant cells can change their identities to evade the therapies we design.

"Plasticity... represents a formidable challenge for treating cancer because it means that malignant cells can change their identities to evade the therapies we design."

We now believe that reversing the cells' new identities is the key to improving response to treatment."

With new funding from the Mark Foundation, the team is starting to uncover ways that bladder cancer cells shift identity and have already identified a potential treatment strategy that restores the cells to their original states. This work builds on a decades-long collaboration between Columbia researchers Michael Shen, Jim McKiernan, and Hanina Hibshoosh, which was the first to report (in Cell, 2018) bladder cancer's ability to change cellular identity and provided the basis for the Mark Foundation's initial support in 2020.

We spoke with members of the team-Cory Abate-Shen, Michael Shen, and Anil Rustgi, director of the Herbert Irving Comprehensive Cancer Center-about their efforts and expansion into the study of esophageal cancers with the new Mark Foundation Center for Lineage Plasticity.

Q: What has your team found about bladder cancer that gives you hope that better treatments could emerge from your research?

Abate-Shen: Not long before we established our team, the field's understanding about the origin of invasive bladder cancer changed considerably. We used to think that the invasive cancers were distinct from the usually treatable forms that stay within the bladder. But then several studies revealed that non-invasive cancers can progress into invasive cancers.

That put the field on the right track, but raised other important questions: what causes this progression and which patients with non-invasive cancers are at greatest risk?

In our team's first years, we established the largest biobank of bladder cancer organoids from patients to help us investigate these questions. These organoids are little spheres of cells in a dish that behave like the patient's original cancer; with them we're able to more easily study tumor progression and treatment response.

In the work we reported in Cell, we found that lineage plasticity is a key mechanism of progression to the invasive type of bladder cancer. In other words, the cancer starts in the bladder's luminal cells but then acquires traits of the bladder's basal cells, which makes the cancer more invasive.

We've also shown that this luminal to basal plasticity is closely associated with certain mutations, and that led us to identify a drug that can reverse the changes in cell identity and potentially make the tumors more treatable. A major focus of the Mark Center grant is to establish clinical trials that will allow us to test this concept in patients.

We're optimistic that this line of research will lead to better treatments down the road. In fact, lineage plasticity is now a hot area in the field of cancer research, and I recently chaired a completely packed session devoted to this topic at the recent American Association of Cancer Research annual meeting in Chicago.

Q: What are you hoping to find next?

Michael Shen: Our goal is to apply the insights from these basic studies to develop a clinical trial with patients that will evaluate whether reversal of plasticity improves outcomes.

"If we can turn invasive basal cells back into luminal cells... antibody therapies may target tumor cells more accurately."

We're particularly excited about combining the drug we've identified with new antibody-based therapies that deliver anticancer drugs directly into bladder cancer cells. These new antibody therapies find cancer cells by recognizing specific proteins on the cancer cells' surface, but these proteins are only found on luminal cells, not basal cells. That means that if we can turn invasive basal cells back into luminal cells, these antibody therapies may target tumor cells more accurately.

We'll also be diving further into data from our organoids, as well as publicly available data on patient tumors, to find other mechanisms that drive bladder cell plasticity. We'll then use this information to identify additional drug candidates to reverse the transition.

Q: With the new funding from the Mark Foundation, you're also bringing in researchers who study esophageal cancer. What's the connection between bladder and esophageal cancers?

Anil Rustgi: Although the bladder and esophagus appear to be distinct and anatomically separate tissues, they share an origin in development and have similar functions. Both tissues are designed to protect themselves against damaging insults-gastric reflux for the esophagus, urea for the bladder. And in both tissues, smoking is believed to be a major inducer of cancers, which originate in the basal cells of both tissues.

"Our trainees realized that the mechanism of luminal-to-basal plasticity in bladder cancer is similar to the plasticity observed in esophageal squamous cell carcinoma."

It just so happens that my lab, which studies esophageal cancer, is on the same floor as Michael's. Cory calls this the "power of proximity." Our trainees were talking about their new findings and they realized the potential connections that were previously unforeseen. This was really an "aha" moment which catalyzed the formation of the Mark Foundation team and guided the conceptual basis for the overall project.

Our trainees realized that the mechanism of luminal-to-basal plasticity in bladder cancer is similar to the plasticity observed in esophageal squamous cell carcinoma and even uses several of the same genes. This key insight will allow us to extend our clinical trials to esophageal squamous cell carcinoma as well as bladder cancer.

By focusing on the intersection of these two seemingly different cancers, we hope to establish general principles of plasticity in cancer and discover therapeutic approaches that may apply to both cancers, and possibly other cancers as well.

More information

Cory Abate-Shen, PhD, is professor of molecular pharmacology and therapeutics and the Robert Sonneborn Professor of Medicine, with additional appointments in the Departments of Urology and Systems Biology at the Vagelos College of Physicians and Surgeons. She is also a member of the Herbert Irving Comprehensive Cancer Center and the Institute for Cancer Genetics at Columbia University.

Michael Shen, PhD, is the Arthur J. Antenucci Professor of Medical Sciences in the Department of Medicine at Columbia University Vagelos College of Physicians and Surgeons, with additional appointments in the Department of Genetics and Development, Urology, and Systems Biology. He is co-leader of the Tumor Biology and Microenvironment Program at the Herbert Irving Comprehensive Cancer Center.

Anil Rustgi, MD, is the Herbert and Florence Irving Director of the Herbert Irving Comprehensive Cancer Center; Herbert and Florence Irving Professor of Medicine; associate dean of oncology; and special advisor, cancer programs and strategies at Columbia University.