Review Series
Abstract
Pancreatic cancer (PC) is a devastating disease, due in part to its diagnosis frequently being made at an advanced stage. Ongoing efforts are aimed at identifying early-stage PC in high-risk individuals, as early detection leads to downstaging of PC and improvements in survival. However, there are a myriad of challenges that arise when trying to optimize PC early detection strategies, including selection of the appropriate high-risk individuals and selection of the test or combination of tests that should be performed. Here, we discuss the populations that are the strongest candidates for PC screening and review professional PC screening guidelines. We also summarize the current state of imaging techniques for early detection of PC and further review many studied biomarkers — ranging from nucleic acid targets, proteins, and the microbiome — to highlight the current state of the field and the challenges that remain in the years to come.
Authors
Michael J. Shen, Arsia Jamali, Bryson W. Katona
Abstract
The gut microbiota plays a crucial role in maintaining intestinal homeostasis and influencing various aspects of host physiology, including immune function. Recent advances have highlighted the emerging importance of the complement system, particularly the C3 protein, as a key player in microbiota-host interactions. Traditionally known for its role in innate immunity, the complement system is now recognized for its interactions with microbial communities within the gut, where it promotes immune tolerance and protects against enteric infections. This Review explores the gut complement system as a possibly novel frontier in microbiota-host communication and examines its role in shaping microbial diversity, modulating inflammatory responses, and contributing to intestinal health. We discuss the dynamic interplay between microbiota-derived signals and complement activation, with a focus on the C3 protein and its effect on both the gut microbiome and host immune responses. Furthermore, we highlight the therapeutic potential of targeting complement pathways to restore microbial balance and treat diseases such as inflammatory bowel disease and colorectal cancer. By elucidating the functions of the gut complement system, we offer insights into its potential as a target for microbiota-based interventions aimed at restoring intestinal homeostasis and preventing disease.
Authors
Xianbin Tian, Lan Zhang, Xinyang Qian, Yangqing Peng, Fengyixin Chen, Sarah Bengtson, Zhiqing Wang, Meng Wu
Abstract
The complement system has emerged as a critical regulator of intestinal homeostasis, inflammation, and cancer. In this Review, we explore the multifaceted roles of complement in the gastrointestinal tract, highlighting its canonical and noncanonical functions across intestinal epithelial and immune cells. Under homeostatic conditions, intestinal cells produce complement that maintains barrier integrity and modulates local immune responses, but complement dysregulation contributes to intestinal inflammation and promotes colon cancer. We discuss recent clinical and preclinical studies to provide a cohesive overview of how complement-mediated modulation of immune and nonimmune cell functions can protect or exacerbate inflammation and colon cancer development. The complement system plays a dual role in the intestine, with certain components supporting tissue protection and repair and others exacerbating inflammation. Intriguingly, distinct complement pathways modulate colon cancer progression and response to therapy, with novel findings suggesting that the C3a/C3aR axis constrains early tumor development but may limit antitumor immunity. The recent discovery of intracellular complement activation and tissue-specific complement remains vastly underexplored in the context of intestinal inflammation and colon cancer. Collectively, complement functions are context- and cell-type-dependent, acting both as a shield and a sword in intestinal diseases. Future studies dissecting the temporal and spatial dynamics of complement are essential for leveraging its potential as a biomarker and therapeutic in colon cancer.
Authors
Carsten Krieg, Silvia Guglietta
Abstract
The complement system is an evolutionarily conserved host defense system that has evolved from invertebrates to mammals. Over time, this system has become increasingly appreciated as having effects beyond purely bacterial clearance, with clinically relevant implications in transplantation, particularly lung transplantation. For many years, complement activation in lung transplantation was largely focused on antibody-mediated injuries. However, recent studies have highlighted the importance of both canonical and noncanonical complement activation in shaping adaptive immune responses, which influence alloimmunity. These studies, together with the emergence of FDA-approved complement therapeutics and other drugs in the pipeline that function at different points of the cascade, have led to an increased interest in regulating the complement system to improve donor organ availability as well as improving both short- and long-term outcomes after lung transplantation. In this Review, we provide an overview of the when, what, and how of complement in lung transplantation, posing the questions of: when does complement activation occur, what components of the complement system are activated, and how can this activation be controlled? We conclude that complement activation occurs at multiple stages of the transplant process and that randomized controlled trials will be necessary to realize the therapeutic potential of neutralizing this activation to improve outcomes after lung transplantation.
Authors
Hrishikesh S. Kulkarni, John A. Belperio, Carl Atkinson
Abstract
Metabolic dysfunction–associated steatohepatitis (MASH) is a progressive form of liver disease characterized by hepatocyte injury, inflammation, and fibrosis. The transition from metabolic dysfunction–associated steatotic liver disease (MASLD) to MASH is driven by the accumulation of toxic lipid and metabolic intermediates resulting from increased hepatic uptake of fatty acids, elevated de novo lipogenesis, and impaired mitochondrial oxidation. These changes promote hepatocyte stress and cell death, activate macrophages, and induce a fibrogenic phenotype in hepatic stellate cells (HSCs). Key metabolites, including saturated fatty acids, free cholesterol, ceramides, lactate, and succinate, act as paracrine signals that reinforce inflammatory and fibrotic responses across multiple liver cell types. Crosstalk between hepatocytes, macrophages, and HSCs, along with spatial shifts in mitochondrial activity, creates a feed-forward cycle of immune activation and tissue remodeling. Systemic inputs, such as insulin-resistant adipose tissue and impaired clearance of dietary lipids and branched-chain amino acids, further contribute to liver injury. Together, these pathways establish a metabolically driven network linking nutrient excess to chronic liver inflammation and fibrosis. This Review outlines how coordinated disruptions in lipid metabolism and intercellular signaling drive MASH pathogenesis and provides a framework for understanding disease progression across tissue and cellular compartments.
Authors
Gregory R. Steinberg, Andre C. Carpentier, Dongdong Wang
Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD), now the most common cause of chronic liver disease, is estimated to affect around 30% of the global population. In MASLD, chronic liver injury can result in scarring or fibrosis, with the degree of fibrosis being the best-known predictor of adverse clinical outcomes. Hence, there is huge interest in developing new therapies to inhibit or reverse fibrosis in MASLD. However, this has been challenging to achieve, as the biology of fibrosis and candidate antifibrotic therapeutic targets have remained poorly described in patient samples. In recent years, the advent of single-cell and spatial omics approaches that can be applied to human samples have started to transform our understanding of fibrosis biology in MASLD. In this Review, we describe these technological advances and discuss the new insights such studies have provided, focusing on the role of epithelial cell plasticity, mesenchymal cell activation, scar-associated macrophage accumulation, and inflammatory cell stimulation as regulators of liver fibrosis. We also consider how omics techniques can enhance our understanding of evolving concepts in the field, such as hot versus cold fibrosis and the mechanisms of liver fibrosis regression. Finally, we touch on future developments and how they are likely to inform a more mechanistic understanding about how fibrosis might differ between patients and how this could influence optimal therapeutic approaches.
Authors
Fabio Colella, Neil C. Henderson, Prakash Ramachandran
Abstract
Inflammatory bowel diseases (IBDs) are complex immune disorders that arise at the intersection of genetic susceptibility, environmental exposures, and dysbiosis of the gut microbiota. Our understanding of the role of the microbiome in IBD has greatly expanded over the past few decades, although efforts to translate this knowledge into precision microbiome-based interventions for the prevention and management of disease have thus far met limited success. Here we survey and synthesize recent primary research in order to propose an updated conceptual framework for the role of the microbiome in IBD. We argue that accounting for gut microbiome context — elements such disease regionality, phase of disease, diet, medication use, and patient lifestyle — is essential for the development of a clear and mechanistic understanding of the microbiome’s contribution to pathogenesis or health. Armed with better mechanistic and contextual understanding, we will be better prepared to translate this knowledge into effective and precise strategies for microbiome restitution.
Authors
Megan S. Kennedy, Eugene B. Chang
Abstract
Pancreatic cancer has a 5-year survival rate of approximately 13% and is projected to become the second-leading cause of cancer-related deaths by 2040. Despite advances in preclinical research, clinical translation remains challenging, and combination chemotherapy remains the standard of care. The intrinsic heterogeneity of pancreas cancer underscores the potential of precision medicine approaches to improve patient outcomes. However, clinical implementation faces substantial challenges, including patient performance status, metastatic disease at diagnosis, intrinsic drug resistance, and a highly complex tumor microenvironment. Emerging targeted therapies, such as RAS inhibitors, offer promise for personalized treatment. These developments have prompted precision medicine–focused clinical trials using molecular subtyping for patient stratification. Effective development of precision medicine therapies depends heavily on robust preclinical models capable of accurately recapitulating the complexities of the pancreatic tumor microenvironment. Two-dimensional, air-liquid interface, and patient-derived organoid cultures combined with in vivo genetically engineered mouse models and patient-derived xenografts represent valuable experimental systems. This Review critically examines the strengths and limitations of these experimental model systems. We highlight their relevance and utility for advancing precision medicine strategies in pancreas cancer.
Authors
Vasiliki Pantazopoulou, Casie S. Kubota, Satoshi Ogawa, Kevin Christian Montecillo Gulay, Xiaoxue Lin, Hyemin Song, Jonathan R. Weitz, Hervé Tiriac, Andrew M. Lowy, Dannielle D. Engle
Abstract
The genetic landscape of pancreatic ductal adenocarcinoma (PDAC) is well-established and dominated by four key genetic driver mutations. Mutational activation of the KRAS oncogene is the initiating genetic event, followed by genetic loss of function of the CDKN2A, TP53, and SMAD4 tumor suppressor genes. Disappointingly, this information has not been leveraged to develop clinically effective targeted therapies for PDAC treatment, where current standards of care remain cocktails of conventional cytotoxic drugs. Nearly all (~95%) PDAC harbors KRAS mutations, and experimental studies have validated the essential role of KRAS mutation in PDAC tumorigenic and metastatic growth. Identified in 1982 as the first gene shown to be aberrantly activated in human cancer, KRAS has been the focus of intensive drug discovery efforts. Widely considered “undruggable,” KRAS has been the elephant in the room for PDAC treatment. This perception was shattered recently with the approval of two KRAS inhibitors for the treatment of KRASG12C-mutant lung and colorectal cancer, fueling hope that KRAS inhibitors will lead to a breakthrough in PDAC therapy. In this Review, we summarize the key role of aberrant KRAS signaling in the biology of pancreatic cancer; provide an overview of past, current, and emerging anti-KRAS treatment strategies; and discuss current challenges that limit the clinical efficacy of directly targeting KRAS for pancreatic cancer treatment.
Authors
Kristina Drizyte-Miller, Taiwo Talabi, Ashwin Somasundaram, Adrienne D. Cox, Channing J. Der
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal cancers, with metastasis as the primary driver of mortality. While metastatic mechanisms are shared across malignancies, PDAC metastasis poses unique therapeutic challenges due to the presence of extensive tumor heterogeneity, desmoplasia, and immunosuppression — features that enable diverse migratory behaviors and therapeutic resistance. Recent advances have shown that metastatic progression in PDAC emerges from dynamic interactions between tumor cell–intrinsic and microenvironmental factors, each adapting to evolving stressors throughout the metastatic cascade. In the primary tumor, genomic instability and epigenetic reprogramming generate subclones with heightened invasive potential, while dense stromal reactions and myeloid-dominated immune suppression facilitate escape. During circulation, PDAC cells employ distinctive survival strategies through homotypic clustering and heterotypic interactions with blood components. At distant sites, PDAC cells adapt to organ-specific microenvironments through context-dependent metabolic and immune modulation, resulting in phenotypes that diverge from the primary tumor. In this Review, we examine how tumor-stroma crosstalk mechanisms shape metastatic progression in PDAC, provide a framework for understanding why conventional therapies often fail against metastatic disease, and highlight emerging opportunities for stage- and site-specific therapeutic interventions that target these unique adaptations.
Authors
Ravikanth Maddipati
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