Dr. Papagiannakopoulos’s research is pioneering in its examination of how cancer cells adapt metabolically to stressful environments, rewiring nutrient and energy utilization pathways to survive and evade immune destruction. His laboratory employs sophisticated genome editing tools and functional genetic screens in living models, an approach that allows precise dissection of the molecular drivers of tumor progression. This methodology is crucial in distinguishing which genetic aberrations are cancer’s true vulnerabilities, offering promising avenues for the development of targeted therapies.

What sets Dr. Papagiannakopoulos apart is his integrative focus that spans metabolism and immunology, fields traditionally studied in isolation. His work elucidates how metabolic rewiring in tumor cells not only supports survival but actively shapes the immune milieu within and beyond the tumor microenvironment. By understanding these dynamic interactions, his research opens the door to manipulating tumor metabolism and immune responses concurrently, a strategy that could revolutionize anti-cancer treatments.

A novel dimension of his research investigates the crosstalk between tumors and the nervous system. Dr. Papagiannakopoulos and his team explore how cancer cells influence brain and peripheral nerve functions to modulate tumor growth, metabolic pathways, and immune system behavior. These interactions have significant clinical implications as they contribute to the cachexia syndrome frequently observed in cancer patients—manifesting as fatigue, anorexia, and severe weight loss—and currently represent a major therapeutic challenge.

Dr. Papagiannakopoulos’s involvement in the InteroCANCEption project, backed by a prestigious Cancer Grand Challenges grant, aims to decode the mechanisms by which the nervous system senses and responds to cancer throughout the body. This systemic approach to cancer biology underscores the emerging paradigm that cancer should be understood not only as a cellular and genetic disease but also as a complex disorder modulated by whole-body physiological networks.

Commenting on the appointment, Salk Institute President Gerald Joyce highlighted Dr. Papagiannakopoulos’s talent for bridging fundamental cancer biology with innovative, interdisciplinary strategies. Joyce emphasized that this alignment with Salk’s culture of curiosity-driven research and collaboration exemplifies the Institute’s mission to pioneer foundational science with the potential to yield transformative clinical breakthroughs.

Dr. Papagiannakopoulos expressed enthusiasm about joining the Salk Institute, citing its unique environment where high-risk, high-reward science thrives. He underscored the significance of integrating his expertise with the existing strengths in cancer immunobiology, metabolism, and neurobiology at Salk, particularly collaboration opportunities with the NOMIS Center and neuroscientists focusing on how cancer intersects with systemic physiology.

Among his groundbreaking contributions, Dr. Papagiannakopoulos’s recent publications in Nature unveiled therapeutic potentials by targeting proteins involved in ferroptosis resistance and immune evasion in lung and pancreatic cancer models. Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, represents an Achilles’ heel for certain tumors—disabling mechanisms that prevent ferroptosis can trigger cancer cell death. Similarly, inhibiting proteins that suppress anti-tumor immune responses unveils new immunotherapeutic strategies that could complement existing treatments, broadening the arsenal against aggressive cancers.

Dr. Papagiannakopoulos’s academic journey is distinguished by rigorous training, beginning with a Bachelor’s degree in Molecular Genetics from the University of Sussex, followed by a PhD in Molecular and Cellular Biology at the University of California, Santa Barbara. His postdoctoral work at MIT sharpened his expertise in genome engineering techniques and in vivo cancer modeling. Throughout his career, his innovative research has attracted significant funding from federal and philanthropic sources, including the National Institutes of Health and the American Cancer Society.

At the Salk Institute, Dr. Papagiannakopoulos aims to establish a multidisciplinary research program that emphasizes integrative cancer biology, emphasizing the complex interplay between genetic mutations, cellular metabolism, immune surveillance, and neural regulation. His work will further energize Salk’s Conquering Cancer Initiative, which coordinates researchers across diverse fields to develop innovative strategies targeting lethal cancers, with a focus on lung cancer among others.

Reuben Shaw, PhD, director of Salk’s NCI-Designated Cancer Center, praised Dr. Papagiannakopoulos’s rare blend of experimental prowess and biological insight. Shaw highlighted how his innovative use of in vivo genetic modeling combined with deep knowledge of tumor metabolism and immune responses, along with a novel focus on cancer’s brain-body interactions, will greatly enhance the Center’s mission to identify new cancer vulnerabilities. Beyond research, Papagiannakopoulos is also recognized as a dedicated mentor, poised to inspire the next generation of cancer scientists at Salk.

This appointment signals a bold expansion of Salk’s cancer research capabilities, poised to unravel the multifaceted nature of cancer biology. By converging metabolism, immunology, and neurobiology, Dr. Papagiannakopoulos’s interdisciplinary vision promises not only to accelerate basic scientific understanding but also to accelerate the translation of discoveries into novel, effective therapies, potentially transforming cancer treatment paradigms.

The Salk Institute itself, founded in 1960 by Jonas Salk—the developer of the first safe polio vaccine—continues its mission of pioneering foundational and high-impact biological research. Its commitment to risk-taking, curiosity-driven science remains a beacon for innovation, addressing some of society’s most urgent health challenges, including cancer. Dr. Papagiannakopoulos’s recruitment exemplifies the Institute’s ongoing leadership in marrying foundational science with translational prospects that can change medicine globally.

As Dr. Papagiannakopoulos embarks on this next chapter at Salk, the scientific community eagerly anticipates the groundbreaking discoveries that will emerge from his integrative and visionary approach to cancer biology. These efforts not only deepen our molecular understanding of cancer but also pave pathways toward innovative therapeutic interventions that may one day cure or effectively manage certain cancers that currently pose formidable clinical challenges.

Subject of Research: Cancer biology, tumor metabolism, cancer immunology, tumor-host interactions, cancer neuroscience

Article Title: Salk Institute Welcomes Dr. Thales Papagiannakopoulos to Advance Cancer Research Frontier

News Publication Date: April 2, 2026

Web References:

• Salk Institute: www.salk.edu
• InteroCANCEption Project: Cancer Grand Challenges

References:

• Papagiannakopoulos et al., Nature, recent studies on ferroptosis and anti-tumor immunity (specific citations not provided in source text)

Image Credits: Sim Singh

Keywords: Cancer metabolism, immunology, tumor microenvironment, ferroptosis, genome engineering, nervous system and cancer, tumor-host interactions, Salk Institute, lung cancer, pancreatic cancer, cancer neuroscience, cancer therapy

Ferroptosis, distinct from other types of cell death such as apoptosis or necrosis, is characterized by the overwhelming peroxidation of lipids within the cell membrane, leading to catastrophic structural failure and cell demise. Central to the regulation of this lethal pathway are antioxidant systems that cancer cells can leverage to prevent this oxidative damage. FSP1 acts as a formidable guardian, mitigating the lipid peroxidation that triggers ferroptosis. This study demonstrates for the first time that metastatic melanoma cells colonizing lymph nodes become heavily reliant on FSP1, underscoring its importance as a defense mechanism in these novel microenvironments.

The implications of these findings are profound. Metastasis—the spread of cancer cells from the primary tumor to distant organs or tissues—is the primary cause of cancer-related mortality. Yet, much of the research to date has focused predominantly on primary tumor biology, often neglecting the unique challenges and selective pressures cancer cells encounter in metastatic niches such as the lymphatic system. By investigating melanoma metastases within the lymph nodes of live mouse models, the researchers highlight the dynamic interplay between tumor cells and their local environments, revealing a context-dependent shift in survival strategies that could be specifically targeted therapeutically.

Remarkably, when experimental compounds designed to inhibit FSP1 were administered to these melanoma metastases in vivo, researchers observed a significant suppression of tumor growth. This effect starkly contrasted with results from conventional in vitro experiments, where cultured melanoma cells grown on plastic surfaces displayed minimal sensitivity to the same inhibitors. The discrepancy underscores the critical role of the microenvironment in governing tumor cell susceptibility and suggests that preclinical drug evaluations should prioritize in vivo models that faithfully recapitulate the complex biological context of human cancers.

This study further challenges the prevailing notion that ferroptosis regulation in cancer cells is uniform across all contexts, instead emphasizing a highly tissue-specific dependency. The lymph node milieu appears to shape the metabolic demands and antioxidant defenses of metastatic melanoma cells, selectively steering their reliance toward FSP1—an insight that could revolutionize how oncologists think about and approach the treatment of metastatic disease. It points to the possibility that precision oncology may require not only targeting specific genetic alterations but also tailoring therapies to the ecological niche of metastatic tumors.

Jessalyn Ubellacker, assistant professor of molecular metabolism and the study’s corresponding author, stresses the transformative potential of these findings. She elaborates that targeting ferroptosis defense mechanisms, once considered an abstract strategy, now emerges as a tangible and viable approach to impeding cancer progression. This represents a shift toward exploiting the adaptive weaknesses that cancer cells acquire as they colonize new organs, potentially leading to treatments that are both more specific and less toxic.

Importantly, the study was conducted using advanced in vivo cancer metastasis models, enabling the researchers to capture the authentic physiological and biochemical interactions that occur within the lymphatic environment. Such models are indispensable tools to unravel the complexity of tumor adaptation during metastasis and provide a powerful platform for the evaluation of novel therapeutic candidates. The insight gained here is emblematic of the growing trend in cancer research toward more physiologically relevant experimental frameworks.

Complementing this work, a concurrent study from the Papagiannakopoulus Laboratory at New York University corroborates the therapeutic promise of FSP1 inhibition. Their research demonstrates that targeting FSP1 in lung cancer cells similarly provokes ferroptotic cell death and retards tumor growth, suggesting that FSP1’s role as a ferroptosis suppressor transcends cancer types and could be harnessed broadly across oncology. Together, these studies bolster a compelling case for the clinical development of FSP1 inhibitors as next-generation cancer therapeutics.

The development of the FSP1 inhibitors utilized in the Harvard-led study arose from pioneering efforts in Dr. Marcus Conrad’s laboratory at Helmholtz Munich and Dr. James Olzmann’s laboratory at the University of California, Berkeley. These highly specialized compounds represent a significant advancement in the pharmacological targeting of ferroptosis regulators. Their successful use in animal models signifies an important step toward translation into human clinical trials, potentially revolutionizing treatment options for patients afflicted with metastatic melanoma and other cancers reliant on ferroptosis suppression.

Cancer metastasis is notoriously difficult to treat and is the leading cause of mortality among cancer patients worldwide. Insights into how metastatic cells reprogram their antioxidant defenses reveal vulnerabilities that have long been overlooked. The discovery that the lymph node microenvironment enforces a dependency on FSP1 underscores the necessity of contextual cancer biology studies, which consider not only cancer cell-intrinsic factors but also tumor-host interactions that influence therapeutic response.

This research and its findings highlight future directions not only for drug development but also for clinical oncology strategies, advocating for therapies tailored to the metastatic site rather than a one-size-fits-all approach to cancer treatment. As metastatic tumors remodel their survival tactics based on their environment, an intricate understanding of these adaptations will be vital in overcoming therapeutic resistance and improving patient outcomes.

Funded by a consortium of prestigious institutions including the Ludwig Center at Harvard, the Melanoma Research Foundation, and multiple NIH grants, this pivotal study marks a crucial milestone in cancer metabolism research and therapeutic innovation. The findings are set to launch a new chapter in the fight against metastatic melanoma and potentially other cancers, driven by an intimate knowledge of ferroptosis biology orchestrated by the tumor microenvironment.

In conclusion, the Harvard T.H. Chan School of Public Health-led team has provided compelling evidence that targeting ferroptosis defense, particularly by inhibiting FSP1 in metastatic melanoma cells within the lymph nodes, offers a promising avenue for therapeutic intervention. By redefining cancer cell death through the lens of tissue-specific dependencies, this work paves the way for the development of highly targeted, effective treatments aimed at one of the most challenging facets of cancer management: metastasis.

Subject of Research: Lab-produced tissue samples

Article Title: Lymph node environment drives FSP1 targetability in metastasizing melanoma

News Publication Date: November 5, 2025

Web References: http://dx.doi.org/10.1038/s41586-025-09709-1

References: Palma M, Chaufan M, Breuer CB, et al. Lymph node environment drives FSP1 targetability in metastasizing melanoma. Nature. 2025 Nov 5. doi:10.1038/s41586-025-09709-1.

Keywords: Cancer, Metastasis, Melanoma, Cancer cells, Melanoma cells, Cancer medication, Lymph nodes

The study, published on May 29 in the journal Redox Biology, is spearheaded by doctoral candidate Austin C. MacMillan and senior investigator Tom Cunningham, PhD, whose laboratory focuses on deciphering the complex biochemical pathways driven by oncogenes. MYC, often described as a master regulator, revs up the metabolic machinery of cancer cells, fueling their explosive growth. However, despite extensive knowledge about the individual pathways influenced by MYC, the precise orchestration and coordination of these metabolic networks have remained elusive, particularly their role in manipulating the redox state of lymphoma cells.

At the heart of redox biology lies the delicate equilibrium between oxidative and reductive processes—an essential balance for cell function and survival. Cells maintain this balance through a tightly regulated exchange of electrons, akin to a cellular battery cycling between charged and discharged states. An oxidative state reflects electron loss, while a reductive state reflects electron gain. Cancer cells, under the influence of MYC, manipulate this redox balance to prevent oxidative damage and sustain unchecked proliferation. Disrupting this homeostasis offers a promising avenue to selectively weaken or kill cancer cells without harming normal tissue.

The research team focused on a pivotal enzyme complex known as phosphoribosyl pyrophosphate synthetase (PRPS), which exists in two isoforms in lymphoma cells: PRPS1 and PRPS2. These enzymes regulate the synthesis of phosphoribosyl pyrophosphate (PRPP), a key metabolite for nucleotide biosynthesis and other crucial cellular functions. Utilizing cutting-edge CRISPR-Cas9 gene-editing technology, the researchers selectively knocked out each isoform in lymphoma cell models, enabling them to delineate the distinct and overlapping roles of PRPS1 and PRPS2 in regulating cellular metabolism and redox balance.

The experiments revealed that while both PRPS1 and PRPS2 are vital to lymphoma pathophysiology, they perform differential yet collaborative roles within a biochemical complex profoundly impacting cellular redox homeostasis. Notably, PRPS2 expression and activity were significantly upregulated in lymphoma cells with MYC overexpression, suggesting that MYC co-opts this enzyme complex to remodel metabolic fluxes for its oncogenic agenda. This remodeling alters redox buffering capacity, helping cancer cells to tolerate oxidative stress inflicted by their rapid growth and hostile microenvironment.

Dr. MacMillan elaborates on the surprising discovery that modulation of a single enzymatic step by PRPS can induce widespread alterations in cellular redox states. “We typically expect metabolic networks to exhibit substantial redundancy and buffering capacity, making it rare for one enzymatic activity to exert such global influence.” Yet, the team observed that disrupting PRPS1 heightened cellular sensitivity to oxidative stress, culminating in increased damage within lymphoma cells, whereas abrogation of PRPS2 led to a paradoxical shift toward reductive stress—an accumulation of reducing equivalents that can itself be cytotoxic.

Understanding this dualistic role is pivotal because it demonstrates that MYC-driven lymphoma cells rely on a finely tuned PRPS complex to maintain redox equilibrium, which is essential for their survival. Targeting this enzymatic hub holds therapeutic promise. By strategically inhibiting PRPS enzymes, researchers envision pushing lymphoma cells beyond their narrow window of redox tolerance, selectively triggering cell death or sensitizing tumors to existing chemotherapies and novel oxidative stress-inducing agents.

Professor Cunningham highlights the translational potential of these insights: “The interplay between MYC and the PRPS complex offers a unique metabolic vulnerability. Therapeutic strategies that disrupt this interface have the potential to destabilize cancer cell metabolism profoundly.” The team is currently developing molecular tools and small molecule inhibitors to manipulate PRPS activity with precision. Such agents could be integrated into combination therapy regimens aimed at eradicating resistant and aggressive lymphomas characterized by MYC overexpression.

Another intriguing aspect of the study is the identification of PRPS2 loss as one of the rare few genetic manipulations capable of inducing reductive stress. This phenomenon occurs when excessive reducing agents accumulate, perturbing cellular function and leading to a distinct form of stress that can be therapeutically exploited. Because cancer metabolism is notoriously adaptable, having multiple strategies to tip the redox balance abnormally equips researchers with a broader arsenal against lymphoma.

Through preclinical screening, the lab plans to identify additional compounds and molecular pathways that synergize with PRPS inhibition to further destabilize lymphoma cells’ redox systems. These efforts aim to create a new generation of targeted therapies that go beyond broad cytotoxic approaches, minimizing collateral damage and improving patient outcomes. The integration of metabolic and redox biology thus holds promise for highly selective cancer therapeutics.

The publication also clarifies conflict of interest statements: MacMillan and Cunningham have filed a patent application related to this research, underscoring the innovative translational potential of their findings. Other authors involved in the study declared no competing interests. The collaborative team includes Bibek Karki, Juechen Yang, Karmela Gertz, Samantha Zumwalde, Jay Patel, Maria Czyzyk-Krzeska, and Jarek Meller.

Given the critical role of MYC in diverse cancers, the implications of tuning PRPS-mediated redox homeostasis transcend lymphoma and may inspire broader oncological research. The study exemplifies how unraveling metabolic interdependencies can reveal hidden vulnerabilities, providing a conceptual blueprint for next-generation cancer therapies that exploit the bioenergetic and redox peculiarities of tumor cells.

As lymphoma remains a significant clinical challenge with often limited treatment options for aggressive forms, this research represents hope for patients and clinicians alike. By harnessing insights into redox biology and metabolic control, the scientific community advances closer to therapies that not only inhibit cancer growth but do so with precision and adaptability, reducing the burden of side effects and overcoming resistance.

This landmark study highlights the power of combining innovative genetic tools, rigorous biochemical analysis, and an integrative understanding of cancer metabolism. It stands at the forefront of an evolving landscape where cancer treatment transitions from broad-spectrum cytotoxicity to exquisitely targeted metabolic intervention, setting a new paradigm in oncology research.

Subject of Research:
Metabolic regulation and redox homeostasis in MYC-driven lymphoma mediated by phosphoribosyl pyrophosphate synthetase (PRPS) enzyme complex.

Article Title:
PRPS activity tunes redox homeostasis in Myc-driven lymphoma

News Publication Date:
29-May-2025

Web References:
https://doi.org/10.1016/j.redox.2025.103649

Image Credits:
Photo: University of Cincinnati

Keywords:
Lymphoma, Cancer metabolism, Redox homeostasis, MYC oncogene, PRPS1, PRPS2, CRISPR gene editing, Phosphoribosyl pyrophosphate synthetase, Oxidative stress, Reductive stress, Cancer therapeutics, Metabolic vulnerabilities