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A team of researchers from ChristianaCare and the University of Delaware has uncovered a key early step in how colorectal cancer begins. Their new study shows that a common genetic mutation in colorectal cancer disrupts the colon’s normal tissue renewal process, causing immature cells to build up, tissue structure to break down and early tumors to form. Their findings were published in the journal Cancers.
“This finding changes how we think about the very first steps of colon cancer,” said Bruce Boman, M.D., Ph.D., senior author of the study and a senior researcher at the Cawley Center for Translational Cancer Research at ChristianaCare’s Helen F. Graham Cancer Center & Research Institute. “Instead of cancer starting because cells grow too fast, we found that it may start because the normal tissue renewal process slows down, creating a backup of cells that should have moved on. That backup sets the stage for tumors to grow.”
The study was led by a multidisciplinary team of engineers, mathematicians, pathologists and tumor biologists from four research institutions.
Colorectal cancer is one of the most common and deadly cancers worldwide. According to the World Health Organization, more than 1.9 million people are diagnosed each year, and about 930,000 people die from the disease annually.
How healthy colon tissue renews itself The lining of the colon is constantly renewing itself. Every day, billions of cells are shed and replaced to keep the tissue healthy and working properly. This process depends on a steady cycle. New cells form at the base of tiny pockets called crypts, mature as they move upward, and are eventually shed.
The new study shows how this natural process breaks down when a mutation occurs in a gene called APC, which is altered in about 90 percent of colorectal cancers. Rather than speeding up cell growth, the APC mutation creates a slowdown, or bottleneck, in the colon tissue’s renewal cycle.
According to Boman, this slowdown causes dividing cells to pile up instead of moving through the system as they should. The result is a kind of tumor cell “traffic jam” that leads to distorted tissue and the formation of adenomas, early growths that can become cancerous.
What APC-mutant tissue looks like To see these changes up close, the team compared healthy colon tissue with tissue from patients who have familial adenomatous polyposis, or FAP, an inherited condition caused by APC mutations. The differences were clear:
APC-mutant crypts contained more immature, rapidly dividing cells. Fewer cells matured into specialized cells needed for healthy tissue. The zone where cells divide extended higher than normal. The overall renewal cycle took longer. “These findings are significant because they show how cancer-driving mutations change tissues that normally renew themselves nonstop,” Boman said.
Pairing patient tissue with computer modeling To see how these changes happen over time, the researchers studied patient tissue and used a computer model that shows how colon cells normally grow and renew. When they slowed this renewal process in the model, it matched what they saw in tissue with the APC mutation. Cells became crowded, the structures lost their normal shape, and early tumor-like growths, known as adenomas, began to form.
This confirmed that delayed renewal alone can trigger the earliest changes linked to colon cancer, even before cells appear abnormal under a microscope.
“Our findings show that APC mutation does more than turn on growth signals,” Boman said. “It changes the timing of renewal. Once that timing is off, the tissue becomes vulnerable to structural damage and early tumor growth.”
Building on earlier research This study builds on earlier work by the same team that mapped how healthy colon tissue renews itself. In prior studies, the researchers identified five basic biological rules that guide how colon cells grow, move and replace one another in a steady, organized way.
The new findings show what happens when that system breaks down. A common mutation called APC slows the normal renewal process. Young, stem-like cells begin to build up before they can mature. Over time, that imbalance creates the conditions for early tumor growth.
To pinpoint how these changes unfold, researchers Gilberto Schleiniger, Ph.D., and Christopher Raymond, Ph.D., from the University of Delaware’s Department of Mathematical Sciences paired mathematical models with real patient tissue data. Their work shows that even small delays in cell renewal can push healthy tissue toward cancer.
“This gives us a clearer picture of how cancer can start long before a tumor is visible,” said Schleiniger. “By understanding the rules that keep healthy tissue in balance, we can see where and how things begin to go off track.”
A possible path toward future treatments The findings also point toward a potential new approach to treatment. The researchers found evidence that the disrupted renewal process may trigger a chain reaction that allows pre-cancerous cells to keep copying themselves and fueling tumor growth.
By targeting this process, it may be possible to restore normal renewal timing and healthier tissue structure before cancer becomes established.
“This study shows that cancer isn’t just about rogue cells, but about a system that’s fallen out of rhythm,” said Bruce Boman, M.D., Ph.D. “If we can reset that renewal process, we may be able to prevent or slow early tumor growth before it gains momentum.”
CorriXR Therapeutics, ChristianaCare’s first commercial biotherapeutics spinout, has launched a major collaboration with InhaTarget Therapeutics and Merxin Ltd to develop an inhaled genetic therapy for lung cancer. The goal is to deliver a CRISPR-based treatment straight to tumors in the lungs to improve effectiveness and cut harmful side effects.
A New Way to Treat Lung Cancer Lung cancer remains one of the deadliest cancers worldwide. Squamous cell lung carcinoma, an aggressive form of non-small cell lung cancer, accounts for up to 30% of cases. More than 380,000 people are diagnosed each year, yet the five-year survival rate stays under 15%. Standard chemotherapy and immunotherapy often become less effective, and many patients develop resistance that leaves them with few options and rising toxicity.
CorriXR is taking aim at this problem. Its CRISPR gene editing system targets NRF2, a key driver of treatment resistance. By switching off NRF2, the therapy has the potential to make tumors sensitive to chemotherapy again and give patients a chance at better outcomes. As reported in a recent paper in Molecular Therapy Oncology, researchers at ChristianaCare’s Gene Editing Institute showed in preclinical lung cancer models that disabling NRF2 can resensitize tumors to chemotherapy with minimal off-target effects.
“This partnership is about more than science. It’s about hope for patients,” said Eric Kmiec, Ph.D., founder and CEO of CorriXR Therapeutics and chief scientific officer at ChristianaCare’s Gene Editing Institute.
“Lung cancer patients deserve therapies that work and improve quality of life. By combining our CRISPR-based technology with inhaled delivery, we can target tumors directly and reduce systemic toxicity. Our goal is to make treatment simpler, more effective and less invasive.”
How the Inhaled Delivery System Works The treatment will be given through inhalation using InhaTarget’s lipid nanoparticle formulation delivered by Merxin Ltd’s advanced inhaler platform. The goal is a non-invasive therapy that patients could use at home.
“Combining our pulmonary drug delivery LNP platform with CorriXR’s groundbreaking science and Merxin Ltd’s device technology has the potential to reshape the landscape of lung cancer treatment. We are eager to advance work on this novel combination,” said Frédéric De Coninck, Ph.D., co-founder and CEO of InhaTarget Therapeutics.
Merxin Ltd’s technology is central to the approach. Its inhalers are built to deliver precise, consistent doses straight to the lungs. For this collaboration, Merxin Ltd is adapting its device to handle lipid nanoparticle formulations for the first time in a cancer treatment.
“Our advanced inhaler technology is designed to ensure non-invasive, precise, consistent delivery of novel therapeutics,” said Philippe Rogueda, Ph.D., co-founder and chief business officer of Merxin Ltd. “We are excited to contribute to this vital effort and help bring innovative solutions to patients with lung cancer.”
Why This Matters Patients with squamous cell lung carcinoma often face a fast-moving disease and few treatment choices. A therapy that can reach tumors directly, reduce toxicity and avoid resistance would mark a major shift.
“This collaboration underscores the power of combining innovative science with practical delivery solutions,” said Kmiec. “Our CRISPR-based approach is designed to overcome one of the toughest challenges in oncology: treatment resistance. By partnering with experts in inhalation technology, we are moving closer to a therapy that is not only effective but accessible.”
Studies will begin soon, with a substantial set of results on effectiveness and impact expected by spring 2026.
The National Cancer Institute (NCI) has renewed the Cancer Center Support Grant (CCSG) for The Wistar Institute and ChristianaCare’s Helen F. Graham Cancer Center & Research Institute, awarding $16.3 million over the next five years.
The renewal received an “exceptional” rating — the highest possible — recognizing the strength and impact of a partnership that combines world-class basic science with leading community-based cancer care.
A One-of-a-Kind National Model This collaboration is the only one of its kind in the nation, joining Wistar, an NCI-Designated Basic Cancer Center, with ChristianaCare, one of the country’s premier academic community cancer centers and a National Cancer Institute Community Oncology Research Program. Together, they focus on driving advances against some of the most challenging cancers, including pancreatic, melanoma, breast, lung and ovarian cancers.
The grant supports shared infrastructure, scientific resources and programs that enable researchers and clinicians to work seamlessly across both institutions. By connecting laboratory breakthroughs at Wistar with ChristianaCare’s ability to rapidly apply new approaches in a diverse patient population, the partnership accelerates the path from discovery to care.
NCI highlighted the collaboration’s effectiveness, noting that “the ongoing alliance with the Helen F. Graham Cancer Center & Research Institute is where most clinical translation into active oncology trials is occurring, supported by productive collaboration between Wistar investigators and Graham Cancer Center oncologists.”
Impact on Patients and Community “At ChristianaCare, we are committed to bringing innovation directly to the people we serve. Our collaboration with Wistar connects the best of basic science with the realities of patient care,” said Thomas Schwaab, M.D., Ph.D., Bank of America Endowed Medical Director of the Helen F. Graham Cancer Center & Research Institute. “The NCI’s exceptional score recognizes the promise of this work and the progress we are making together. It is a powerful affirmation that our patients are benefiting from research at the highest level.”
“This renewal from the NCI is proof that we are building a model for how cancer research and community care can come together,” said Nicholas J. Petrelli, M.D., director of the Cawley Center for Translational Cancer Research at the Helen F. Graham Cancer Center & Research Institute and associate director of Translational Research at The Wistar Institute Cancer Center. “Through our partnership with Wistar, patients in Delaware and beyond are gaining access to cutting-edge research and therapies for some of the toughest cancers we face.”
Dario Altieri, M.D., president and CEO of The Wistar Institute and director of its Ellen and Ronald Caplan Cancer Center, added: “An exceptional rating from the NCI is a reflection of the scientific excellence and real-world impact of this partnership. What makes this collaboration unique is its ability to take discoveries in areas such as melanoma and ovarian cancer and bring them rapidly into clinical practice through ChristianaCare.”
NCI underscored the alliance’s reach, noting that “the partnership with the Graham Cancer Center brought cutting-edge cancer research to the community and advanced groundbreaking discoveries to first-in-human oncology clinical trials.”
A Pipeline of Research Advancing Faster Than Ever Research achievements supported by the Wistar—ChristianaCare partnership include:
Advancing multiple Wistar discoveries into investigator-initiated, first-in-human oncology clinical trials, including studies in pancreatic, melanoma, lung, breast and ovarian cancers. Launching joint research programs across several cancer types, with expanding efforts in cancer risk and population health. Increasing access to high-quality biospecimens — including tumor tissue, biopsies and blood samples — that fuel translational research. Strengthening shared scientific infrastructure supporting immunotherapy research, organoid development, xenograft models and molecular profiling. The Wistar—ChristianaCare partnership, established in 2011, has grown into a nationally recognized alliance that bridges science and medicine. With this CCSG renewal, the collaboration will expand research in pancreatic, melanoma, breast, lung and ovarian cancers and continue advancing prevention, early detection and training programs for the next generation of physician—scientists.
The Helen F. Graham Cancer Center & Research Institute depends on grants and community support to keep this work moving forward. To learn more or make a gift, visit Support the Helen F. Graham Cancer Center & Research Institute.
