In metastasis, genetics meet geography, study finds

Mutations that drive the growth and survival of cancer cells can help a primary tumor spread to new sites, but the extent to which they help sustain tumor growth at these metastatic sites has been unclear.

An MSK-led research team — led by first author Kaloyan Tsanov, PhD, a former postdoc at MSK who now heads his own lab at the University of Chicago — looked for answers using one such gene, SMAD4, which is commonly inactivated by mutations in gastrointestinal cancers.

The scientists used a mouse model of pancreatic cancer to study whether metastatic tumors remain dependent on SMAD4 deactivation by turning off the gene in early tumor development and later reactivating it in established metastases. Interestingly, they found reactivating SMAD4 had different effects based on the location of the metastasis. It suppressed liver metastases but encouraged the expansion of lung metastases.

“We found that different organ sites select for different cell types present in the primary tumor, and that this can dramatically alter what they need to remain viable,” says senior study author Scott Lowe, PhD, Chair of the Cancer Biology and Genetics Program at MSK’s Sloan Kettering Institute.

“The broader implication is that the effectiveness of some therapies may not only be related to the gene mutations in the tumors, but also where in the body these tumor cells reside,” Dr. Tsanov adds. Read more in Nature Cancer. 

How regulatory T cells work with sensory nerves in the skin to restrain pain and inflammation

Nerve endings in our skin help protect us by sensing a variety of stimuli, including extreme temperature, physical forces, tissue damage, and infection — and by generating sensations like itching or pain. But a growing body of work suggests that these neuronal cells also help mobilize an immune response when confronted with threats.

New MSK research — led by Alejandra Mendoza, PhD, a postdoc in the lab of senior study author Alexander Rudensky, PhD, at the Sloan Kettering Institute — examined the relationship between regulatory T cells (Tregs) and these peripheral neurons. (Dr. Mendoza is now an assistant professor of immunology and microbiology at Scripps Research.)

Tregs are key immune cells that promote tolerance to “self” and to helpful bacteria, harmless food allergens, and long-term infections. Using mouse models of psoriasis-like inflammation, the research team determined that Tregs play an important role in limiting overactivation of sensory neurons in the skin — thereby limiting inflammation — at the early stages of an infection. The researchers also found that Treg expression of Penk — a gene that encodes a neuropeptide called enkephalin, which produces an analgesic effect — is essential to Treg cells’ ability to help regulate the body’s response to pain.

Overall, the study suggests that Tregs, by acting as a part of a mixed immune cell-neuronal circuit, play a vital role in keeping the body from excessive responses when the skin encounters a new threat. Read more in Science Immunology. (The study was also highlighted in the ScienceAdviser newsletter.)

Studying whether a large language model can adequately summarize cancer patients’ experiences with pain

Patient-reported outcomes (PROs) have become a critical component of clinical research to assess the benefits of new medical therapies, including treatments for cancer. These outcomes include factors that affect a patient’s quality of life, such as fatigue, mood, and pain. PROs are generally collected by asking patients to fill out questionnaires, but researchers, including those at MSK, are studying whether large language models like ChatGPT could help to capture PROs in a patient’s own words.

As part of that effort, an MSK team co-led by outcomes research scientist Talya Salz, PhD, and behavioral scientist Thomas Atkinson, PhD, recently received a grant from the nonprofit Patient-Centered Outcomes Research Institute (PCORI) to study how an algorithm guided by a large language model could help identify themes related to the experience of cancer pain from narrative reports. Using the model, named PainReporter, the team will evaluate the extent to which the themes identified by the model agree with conventional PROs metrics of pain. They will also evaluate how patients perceive the accuracy the PainReporter summary and their experiences using the model. Learn more about this project on the PCORI website.

Proton therapy effective at treating leptomeningeal metastasis

Leptomeningeal metastasis (LM) is a serious condition in which cancer spreads to the fluid and tissues surrounding the brain and spinal cord. New results from a randomized phase 2 clinical trial at MSK show that craniospinal proton therapy, an advanced form of radiation therapy, is effective in controlling LM.

In LM patients who received proton therapy to the brain and spinal cord (also called proton craniospinal irradiation), the disease remained stable more than three times longer than in those who got conventional radiation to just the brain or portions of the spinal cord. Patients receiving proton craniospinal therapy also lived more than twice as long.

Earlier results were presented in 2022 at the annual meeting of the American Society of Clinical Oncology (ASCO) by Jonathan Yang, MD, PhD, who has since left MSK. Dr. Yang collaborated closely with neuro-oncologist Adrienne Boire, MD, PhD, who has devoted her research to finding additional ways to block LM.

“This work shows that it is essential to treat both the brain and the spinal cord when treating LM. It’s very exciting that we have an effective new option for a disease that is very hard to treat,” Dr. Boire says. “Previous radiation techniques did not allow us to treat the brain and spinal cord. These results show that proton therapy should be considered when it is available.” Read more in JAMA Oncology.

            Media Contact

                                Nick Gardner
                Memorial Sloan Kettering Cancer Center
            gardnern@mskcc.org
                Office: 917-843-3834
            Keywords
                          /Scientific community/Research programs/Cancer research
                              /Scientific community/Scientific approaches/Basic research
                               /Scientific community/Scientific approaches/Discovery research
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		https://scienmag.com/march-26-2025-key-advances-in-msk-research-unveiled/
		
		
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		https://scienmag.com/march-26-2025-key-advances-in-msk-research-unveiled/

					
										New research emerging from Memorial Sloan Kettering Cancer Center (MSK) reveals groundbreaking advancements in understanding mitochondrial DNA deletions, the mechanisms behind histiocytosis-associated neurodegeneration, and the surprising way mutant stem cells exploit regenerative processes to promote tumor growth. These studies offer profound insights into the genetic and cellular basis of several critical health issues that have previously eluded effective treatment strategies.

At the forefront of this research is the innovative work conducted in the laboratory of molecular biologist Agnel Sfeir, PhD. His team at MSK’s Sloan Kettering Institute has developed a cutting-edge technique to engineer specific deletions in mitochondrial DNA (mtDNA) within human cells. Mitochondrial DNA, unlike genomic DNA located within the nucleus, has unique properties and vulnerabilities that make it challenging to manipulate experimentally. This new method opens doors to model diseases linked to mtDNA deletions, which are known to manifest in severe disorders that include muscular dystrophies and cardiac complications.
Mitochondria are the cellular powerhouses, generating energy through oxidative phosphorylation. When large-scale deletions occur within mtDNA, the consequences are dire, often leading to debilitating conditions that can significantly compromise patient quality of life. Dr. Sfeir’s lab innovatively drew on techniques from different biological kingdoms, bringing a cross-kingdom approach to solve the challenges posed by mtDNA editing. By borrowing a DNA repair mechanism known as end joining, typically found in bacteria, they successfully integrated this with human enzymes to carry out precise genetic modifications.
The research team managed to create cell lines with substantial mtDNA deletions exceeding 3,500 base pairs. Their findings revealed that cells could tolerate significant genetic loss—up to 75% of their mitochondrial DNA—before manifesting functional weaknesses that lead to diseases. This critical threshold provides a new framework for understanding how cells cope with mtDNA damage and might guide therapeutic strategies aimed at preserving mitochondrial function in patients more effectively.
In parallel, MSK researchers have shed light on Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD), which represent rare but aggressive disorders marked by abnormal proliferation of myeloid cells. Led by research fellow Rocio Vicario, PhD, the investigation unveiled a compelling link between these conditions and neurodegeneration. The study identified that mutated cells in the BRAF gene amass in specific brain regions, initiating a cascade of neurodegenerative damage reminiscent of neuroinflammatory responses.
Significantly, the study uncovered that neurodegenerative indicators could be detected years before the onset of clinical symptoms, suggesting a window for potential therapeutic intervention. Employing mouse models, researchers demonstrated that eliminating inflammatory microglia—cells responding to brain injury—during early degeneration stages reduced inflammation, safeguarded neurons, and positively influenced survival outcomes. This work not only highlights the neurobiological consequences of LCH and ECD but also opens avenues for innovative treatment interventions that could alter disease trajectories.
Meanwhile, in the realm of cancer research, further intriguing findings emerge from the lab of stem cell biologist Joo-Hyeon Lee, PhD. His studies reveal that tumors can mimic the regenerative processes of healing, a phenomenon that has long posed questions about the intersection of tissue regeneration and cancer development. By investigating the role of lung alveolar stem cells carrying the KRAS-G12D mutation, a known driver of lung adenocarcinoma, researchers elucidated how these altered cells commandeer regenerative pathways to perpetuate tumor growth.
What the team discovered was particularly profound: a subset of KRAS mutant stem cells exhibited an enhanced growth capacity within tumor contexts by adopting regenerative programming initially. However, as tumorigenesis progressed, these cells engaged in dysregulated feedback loops that maintained aberrant activation of the NF-kB signaling pathway. This process not only facilitated continuous cell state transitions—fostering an aggressive tumor expansion—but also hindered normal differentiation processes, further complicating treatment efforts.
The implication of these findings resonates deeply within the oncology community, offering fresh perspectives on the evolution of lung adenocarcinomas and potential avenues for therapeutic explorations. Understanding how tumor cells manipulate cellular mechanisms offers crucial insight into developing targeted interventions to curb cancer progression by disrupting these regenerative pathways.
By synthesizing these research findings, we glimpse a future wherein comprehensive understanding paves the way for effective therapeutic strategies in treating complex genetic diseases and certain cancers. With mitochondrial DNA manipulation, early intervention in brain degenerative processes, and insights into tumor regeneration, MSK is steadfastly leading the charge in innovative cancer and genetic research.
As the studies at MSK trigger further inquiries into disease mechanisms and potential treatments, the scientific community remains hopeful. The combination of advanced genetic engineering techniques and a deeper understanding of underlying biological processes holds the promise of ushering in a new era of personalized medicine, where targeted therapies can make previously untreatable ailments manageable.
The collaboration across different scientific disciplines serves as a testament to the innovative spirit thriving within research environments like MSK, where addressing complex medical challenges requires an interdisciplinary approach. Through these efforts, life-altering treatments may soon transition from research laboratory discussions to routine clinical applications, significantly impacting medical practice and patient outcomes across the globe.
In summary, the research emerging from Memorial Sloan Kettering Cancer Center not only advances our understanding of critical biological processes but also illuminates new pathways toward potential therapies for debilitating conditions. With a focus on mitochondrial DNA, neurodegeneration linked to rare blood disorders, and tumor biology, these findings herald a future where science continues to push the boundaries of what is possible in medicine.
Subject of Research: Mitochondrial DNA deletions, histiocytosis-associated neurodegeneration, tumor growth mechanisms

Article Title: Groundbreaking Research from MSK Reveals New Mechanisms in Mitochondrial DNA, Neurodegeneration, and Tumor Growth

News Publication Date: October 2023

Web References: MSKCC

References: Refer to original publications cited within the article for specific studies.

Image Credits: Memorial Sloan Kettering Cancer Center  
Keywords: Mitochondrial DNA, neurodegeneration, tumor growth, cancer research, stem cell research, genetic engineering, therapeutic strategies, Langerhans cell histiocytosis, Erdheim-Chester disease, KRAS mutation.
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