Hunting for the vulnerability in chondrosarcoma by tracing metabolic and genetic links
Authors: Yi-Jun Kim, Hyun Guy Kang, Jin-Hong Kim
Journal: Cell Reports Medicine (2024)

In this Backstory, we narrate our journey in establishing a multidisciplinary team for sarcoma research and uncovering vulnerabilities in chondrosarcoma cells associated with their NAD+ dependencies for survival.1Suh J. Kim H. Min J. Yeon H.J. Hemberg M. Scimeca L. Wu M.R. Kang H.G. Kim Y.J. Kim J.H. et al.Decoupling NAD+ metabolic dependency in chondrosarcoma by targeting the SIRT1–HIF-2α axis.Cell Rep Med. 2024; 5Google Scholar Our findings hold promise for exploitation, yielding a synergistic cytotoxic effect when combined with systemic therapy. In this Backstory, we narrate our journey in establishing a multidisciplinary team for sarcoma research and uncovering vulnerabilities in chondrosarcoma cells associated with their NAD+ dependencies for survival.1Suh J. Kim H. Min J. Yeon H.J. Hemberg M. Scimeca L. Wu M.R. Kang H.G. Kim Y.J. Kim J.H. et al.Decoupling NAD+ metabolic dependency in chondrosarcoma by targeting the SIRT1–HIF-2α axis.Cell Rep Med. 2024; 5Google Scholar Our findings hold promise for exploitation, yielding a synergistic cytotoxic effect when combined with systemic therapy. Despite the breakthroughs in systemic cancer therapy, treatment for chondrosarcoma has stagnated over recent decades. To date, the most effective treatments for chondrosarcoma remain conventional methods, such as extensive surgical resection, with systemic therapy being explored mostly when metastasis is present. In cases of chondrosarcoma with a histologic grade of 3, half the patients die within five years, and among those with metastasis, four out of five succumb to the disease. Hyun Guy often suggested to Jin-Hong to develop an alternative approach to prevent recurrence, particularly when encountering unfortunate cases where the surgery was successful but the disease progressed with repeated recurrences. Chondrosarcomas primarily arise in anatomical sites crucial for mobility, significantly affecting the quality of life of patients. Yi-Jun recalled a young patient who, when confronted with several recurrences of sarcomas in the knee, finally chose to decline further radiation therapy because of concerns regarding radiation-induced contractures. As these examples show, chondrosarcoma has a significant gap between patient demand and the availability of effective treatments, more so than many other cancer types. The lag in the development of systemic therapies for chondrosarcoma is not solely due to its rarity. The heterogeneity of chondrosarcomas presents a formidable challenge in identifying specific treatment targets, rendering strategies effective in other cancers less applicable here. Thus, looking back, making a commitment to establishing a chondrosarcoma research team was a multifaceted challenge. To dissect the mystery of chondrosarcoma, the composition of the research team had to mirror the heterogeneous nature of the tumor. Our team consisted of various specialists in orthopedic surgery, radiation oncology, and basic sciences. Yet, just as we sought a unifying principle to treat this highly heterogeneous tumor, we all shared the common goal of unraveling the complexity of chondrosarcoma to pioneer effective therapeutic approaches. Scientific progress is an ongoing journey, built on cumulative insights. We believe that our recent discovery has been constructed upon an exceptional and extensive foundation of research in the fields of cancer metabolism and chondrosarcoma. The scientific insights gleaned from these studies have been instrumental in guiding our current findings, highlighting the importance of cumulative scientific progress. The discovery of isocitrate dehydrogenase (IDH) mutations is a key breakthrough in chondrosarcoma research.2Amary M.F. Bacsi K. Maggiani F. Damato S. Halai D. Berisha F. Pollock R. O'Donnell P. Grigoriadis A. Diss T. et al.IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours.J. Pathol. 2011; 224: 334-343Crossref PubMed Scopus (773) Google Scholar These mutations, which constitute 50–70% of central or conventional chondrosarcomas, result in the production of 2-hydroxyglutarate (2-HG), an oncometabolite. This oncometabolite, particularly in its D-enantiomer form (D-2-HG), alters the activities of various α-ketoglutarate-dependent enzymes, thereby affecting various cellular metabolism and epigenetic regulation in chondrosarcomas.3Pathmanapan S. Ilkayeva O. Martin J.T. Loe A.K.H. Zhang H. Zhang G.F. Newgard C.B. Wunder J.S. Alman B.A. Mutant IDH and non-mutant chondrosarcomas display distinct cellular metabolomes.Cancer Metabol. 2021; 9: 13Crossref Google Scholar In our previous study, we identified Hypoxia-inducible factor-2α (HIF-2α) as a key regulator governing a characteristic transcription network underlying chondrosarcoma malignancy.4Kim H. Cho Y. Kim H.S. Kang D. Cheon D. Kim Y.J. Chang M.J. Lee K.M. Chang C.B. Kang S.B. et al.A system-level approach identifies HIF-2α as a critical regulator of chondrosarcoma progression.Nat. Commun. 2020; 11: 5023Crossref Scopus (10) Google Scholar Consistent with the notion that D-2-HG is implicated in creating pseudohypoxia by inhibiting prolyl hydroxylases, we found that IDH mutations are, in part, responsible for the increased stability of HIF-2α in chondrosarcoma cells. However, the mechanism behind the selective and robust upregulation of HIF-2α in chondrosarcoma remained an open question for us. In the meantime, we were inspired by two compelling studies that noted the central role of NAD+ pathways in chondrosarcoma cell survival5Peterse E.F.P. van den Akker B.E.W.M. Niessen B. Oosting J. Suijker J. de Jong Y. Danen E.H.J. Cleton-Jansen A.M. Bovée J.V.M.G. NAD Synthesis Pathway Interference Is a Viable Therapeutic Strategy for Chondrosarcoma.Mol. Cancer Res. 2017; 15: 1714-1721Crossref PubMed Scopus (30) Google Scholar and delineated the complexity of NAD+ accumulation mechanisms in cancer cells.6Chowdhry S. Zanca C. Rajkumar U. Koga T. Diao Y. Raviram R. Liu F. Turner K. Yang H. Brunk E. et al.NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling.Nature. 2019; 569: 570-575Crossref PubMed Scopus (127) Google Scholar We hypothesized that chondrosarcomas, characterized by their notable heterogeneity, may display a wide array of NAD+ metabolic dependencies for survival, each leveraging diverse NAD+ synthesis pathways to accumulate NAD+. Timely, the generous contribution of multi-omics data from a large cohort of chondrosarcoma cases by a French group offered valuable clues for testing our hypotheses.7Nicolle R. Ayadi M. Gomez-Brouchet A. Armenoult L. Banneau G. Elarouci N. Tallegas M. Decouvelaere A.V. Aubert S. Rédini F. et al.Integrated molecular characterization of chondrosarcoma reveals critical determinants of disease progression.Nat. Commun. 2019; 10: 4622Crossref PubMed Scopus (48) Google Scholar Indeed, the transcriptional patterns of NAD+ biosynthesis genes clearly distinguished patient cohorts with profoundly contrasting prognoses. Notably, chondrosarcomas with poor prognosis utilized three NAD+ synthesis pathways: the salvage, Preiss-Handler, and de novo pathways. Our next endeavor was to elucidate the role of accumulated NAD+ in sustaining survival signals in chondrosarcomas. Moving a step forward, we set a goal to devise a rational strategy to abolish such NAD+ dependencies for survival, irrespective of the diverse mechanisms of NAD+ accumulation in chondrosarcoma. One of the most thrilling moments of our investigation came when we discovered that two seemingly separate research projects were, in fact, composed of a single common thread: SIRT1. The inhibition of SIRT1 effectively abolished the survival dependency of chondrosarcoma cells on NAD+ metabolism, regardless of the NAD+-accumulating mechanisms employed such as NAMPT and NAPRT overexpression or even glucose deprivation. Our genetic epistasis studies placed HIF-2α as a downstream transcription factor mediating the effect of SIRT1 on chondrosarcoma tumor growth. Collectively, decoupling this link via SIRT1 inhibition exposes chondrosarcoma cells to vulnerabilities imposed by NAD+ dependence, eliciting a synergistic cytotoxic effect in combination with chemotherapy. An intriguing extension of this study was made by the reviewers, who provided insightful comments hinting at the mechanisms underlying the synergism between a SIRT1 inhibitor and a DNA-damaging agent. Treatment with doxorubicin significantly reduced the NAD+/NADH ratio in chondrosarcoma cells, presumably due to the activation of NAD+-dependent DNA repair enzymes, specifically poly(ADP-ribose) polymerases (PARPs), in response to DNA damage. This activation could subsequently increase NAD+ consumption, potentially compromising SIRT1 activity. Further research is warranted to explore the complex reciprocal interactions between DNA-damaging chemotherapy agents and NAD+-dependent enzymes, including SIRT1. Our study provides deeper insight into the intricate dynamics of these metabolic and genetic interactions, which are crucial for advancing our understanding of cancer treatment strategies. Over the course of this study, we believe that our intangible interactions with colleagues from previous studies on chondrosarcoma and the reviewers of our paper have granted us the privilege to stand on the shoulders of giants. Numerous scientists and medical professionals have challenged the perception of cancer as a death sentence. However, sarcomas are often overlooked owing to their rarity and complexity. Patients with sarcomas often find themselves on a metaphorical isolated island awaiting rescue. To end this prolonged wait, Korean researchers, recognizing the need for innovative therapies for sarcomas, formed the Korean Innovative Group for Sarcoma Research (KINGS), which hosted its first symposium last winter. KINGS brings together professionals from various fields such as orthopedics, internal medicine, radiation oncology, pathology, basic science, epidemiology, and data science who share one goal: overcoming sarcoma in partnership with patients. We journey together as we strive for further breakthroughs. While science is a discipline that seeks objectivity, the essence of science is driven by the curiosity and motivation of individuals. In our pursuit of sarcoma research, our team of researchers added a unique motivation. The very disease Jin-Hong had devoted his research to unexpectedly became his personal battle. He suddenly confronted sarcoma not only as a researcher but also from the perspective of a patient living with this condition. Three years ago, Jin-Hong came to know that the bump in his ankle that had been causing discomfort was, in fact, a sarcoma. Hyun Guy stepped into the role of surgeon for Jin-Hong. Yi-Jun analyzed the database from the Surveillance, Epidemiology, and End Results (SEER) and provided him a “probabilistic” comfort based on her findings on his expected prognosis. As a scientist, Jin-Hong was well aware that sarcomas are frequently treatment-refractory. However, this realization took on a new depth of meaning for him when he was diagnosed with sarcoma. For all patients with sarcoma, including Jin-Hong, this means living with the constant anxiety of possible recurrence. We believe that informing patients about the hope of a new treatment option for sarcomas can significantly uplift their motivation to continue their battles against the disease. Jin-Hong is currently in a phase of vigilant follow-up observations, patiently awaiting complete remission. In the meantime, we continue carrying out sarcoma research. Decoupling NAD+ metabolic dependency in chondrosarcoma by targeting the SIRT1-HIF-2α axisSuh et al.Cell Reports MedicineDecember 20, 2023In BriefSuh et al. establish SIRT1 as a central mediator that reinforces the survival dependency of chondrosarcoma cells on NAD+ metabolism through HIF-2α-mediated transcriptional reprogramming. Decoupling this link via SIRT1 inhibition exposes chondrosarcoma cells to vulnerabilities imposed by NAD+ dependencies, eliciting a synergistic cytotoxic effect in combination with chemotherapy. Full-Text PDF Open Access