Oncology
Abstract
Dipeptidase-1 (DPEP1) is highly upregulated in colorectal cancer (CRC), with its enzymatic function linked to invasion and metastasis. More recently, DPEP1 was found to serve as a receptor for neutrophils when expressed by activated endothelial cells. It is unknown whether neutrophils bind to DPEP1-expressing CRC cells and whether this impacts features of CRC. Neutrophils have been shown to be tumor-promoting in cancers including CRC, where they act to exclude CD8+ T cells. Herein, we show that neutrophils bind DPEP1-expressing CRC cells. In addition, DPEP1 is preferentially expressed in microsatellite stable (MSS) CRC, in which there are a paucity of CD8+ T cells, whereas DPEP1 is negatively correlated with microsatellite unstable (MSI-H) CRC, which are T cell-rich and are more responsive to immunotherapy. Remarkably, carcinogen-treated Dpep1 null mice develop multiple, large, plaque-like, locally invasive adenocarcinomas and squamous cell cancers in the distal colon. These adenocarcinomas exhibit a marked reduction of neutrophils and an influx CD8+ T cells, along with reduced expression of mismatch repair proteins, consistent with features of MSI-H CRC. These results establish DPEP1’s importance in maintaining MSS CRC and its ability to shape the tumor microenvironment.
Authors
Sarah E. Glass, Matthew E. Bechard, Zheng Cao, Radhika Aramandla, Ping Zhao, Samuel T. Ellis, Emily H. Green, Elizabeth G. Fisher, Ryan T. Smith, Chelsie K. Sievers, Maria Johnson Irudayam, Frank Revetta, M. Kay Washington, Gregory D. Ayers, Cody N. Heiser, Alan J. Simmons, Yanwen Xu, Yu Wang, Annika Windon, Martha J. Shrubsole, Nicholas O. Markham, Qi Liu, Ken S. Lau, Robert J. Coffey
Abstract
An estimated 5-10% of cancer results from an underlying genetic predisposition, yet for the majority of these cases the genes in question remain unknown, suggesting a critical need to identify new cancer predisposition genes. The protein phosphatase 2A (PP2A) family exists as a trimeric holoenzyme and is a vital negative regulator of multiple oncogenic pathways. PP2A inhibition by somatic mutation, loss of expression, and upregulation of its exogenous inhibitors in tumors has been well described. However, it remains unknown whether germline loss of any PP2A subunits results in a predisposition to cancer in humans. In this study, we identified nine cancer patients with germline loss-of-function (LOF) variants in PPP2R1B (Aβ), the beta isoform of the PP2A scaffold subunit. All four patients for whom documentation was available also had a family history of cancer, including multiple indicators of hereditary cancer. The most highly represented cancer among the Aβ germline patients was breast cancer. Overexpression of these mutant forms of Aβ resulted in truncated proteins that were rapidly turned over. Characterization of an additional missense germline Aβ variant, R233C, that is also recurrently mutated at the somatic level found that it disrupts PP2A catalytic subunit binding resulting in loss of phosphatase activity. An analysis of Aβ expression among multiple breast cancer cohorts revealed that somatic, heterozygous loss of Aβ was a frequent event in this disease and decreased Aβ expression correlated with shorter disease-free and overall survival. Furthermore, Aβ levels were significantly lower in multiple histological subtypes of both in situ and malignant breast cancer compared to adjacent normal breast tissue, suggesting that Aβ loss is an early event in breast cancer development. Together, this highlights a role for Aβ as a predisposition gene in breast cancer and potentially additional cancers.
Authors
Sahar Mazhar, Caitlin M. O’Connor, Alexis Harold, Amanda C. Dowdican, Peter J. Ulintz, Erika N. Hanson, Yuping Zhang, Michelle F. Jacobs, Sofia D. Merajver, Mark W. Jackson, Anthony Scott, Anieta M. Sieuwerts, Arul M. Chinnaiyan, Goutham Narla
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.187073.
Abstract
BACKGROUND. A priori knowledge of recurrence risk in patients with non-metastatic (FIGO stage I) uterine serous carcinoma (USC) would enable a risk-stratified approach to the use of adjuvant chemotherapy. This would greatly reduce treatment-related morbidity and be predicted to improve survival. METHODS. GATA2 expression was scored by immunohistochemistry (IHC) across a retrospective multi-institutional cohort of 195 primary USCs. Associations between GATA2 levels and clinicopathologic metrics were evaluated using Student’s t-test, Fisher’s exact test, Kaplan-Meier method, and Cox proportional hazards ratio. Invasion in patient-derived USC cells was assessed by Student’s t-test. RNA-seq, anti-GATA2 ChIP-seq, and confirmatory western blotting enabled identification of GATA2 targets. RESULTS. Patients with FIGO stage I GATA2high USCs had 100% recurrence-free and 100% cancer related survival, which was significantly better than patients with GATA2low USCs. In patients for whom adjuvant chemotherapy was omitted, patients with GATA2high USC had 100% recurrence free 5-year survival compared to 60% recurrence free survival in patients with GATA2low USC. Depletion of GATA2 in patient-derived USC cells increased invasion in vitro. CONCLUSIONS. Routine GATA2 IHC identifies 33% of FIGO stage I USC patients who have a greatly reduced risk of post-hysterectomy USC recurrence. Our results suggest that a GATA2 guided personalized medicine approach could be rapidly implemented in most hospital settings, would reduce treatment-related morbidity, and likely improve outcomes in USC patients. FUNDING. NIH grants R01 DK068634, P30 CA014520, S10 OD023526, K08 DK127244, T32 HL007899, the UW-Madison Department of Pathology and Laboratory Medicine, the UW-Madison Centennial Scholars Program, the Diane Lindstrom Foundation, the American Cancer Society, the V Foundation, The Hartwell Foundation, and the UMN Department of Obstetrics, Gynecology, and Women's Health.
Authors
Usha S. Polaki, Trey E. Gilpin, Apoorva T. Patil, Emily Chiu, Ruth Baker, Peng Liu, Tatiana S. Pavletich, Morteza Seifi, Paula M. Mañán-Mejías, Jordan Morrissey, Jenna Port, Rene Welch Schwartz, Irene M. Ong, Dina El-Rayes, Mahmoud A. Khalifa, Pei Hui, Vanessa L. Horner, María Virumbrales-Muñoz, Britt K. Erickson, Lisa Barroilhet, Stephanie M. McGregor, Emery H. Bresnick, Daniel R. Matson
Abstract
Non–small cell lung cancer (NSCLC) is a common cause of cancer-related deaths worldwide, and its incidence has been increasing in recent years. While targeted therapies like osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor, have brought about notable improvements in patient outcomes for advanced NSCLC, the challenge of acquired drug resistance persists. Here, we found that cellular mesenchymal-epithelial transition factor (c-Met) was highly expressed in osimertinib-resistant cells, and depletion of c-Met markedly inhibited the growth of osimertinib-resistant cells ex vivo and in vivo, suggesting that c-Met is a potential target to address osimertinib resistance. Through a screening process using a natural product compound library, we identified piperlongumine as a potent inhibitor to overcome osimertinib resistance. Furthermore, the combined treatment of piperlongumine and osimertinib exhibited robust antitumor effects in resistant cells, partially restoring their sensitivity to osimertinib. Additionally, we discovered that piperlongumine could enhance the interaction between E3 ligase RNF4 and Sp1, inhibit the phosphorylation of Sp1 at Thr739, facilitate the ubiquitination and degradation of Sp1, lead to c-Met destabilization, and trigger intrinsic apoptosis in resistant cells. In summary, our study sheds light on the potential of piperlongumine in overcoming osimertinib resistance, offering new strategies and perspectives for the clinical management of drug-resistant NSCLC.
Authors
Ruirui Wang, Qiang Wang, Jinzhuang Liao, Xinfang Yu, Wei Li
Abstract
Hypoxia/hypoxia-inducible factor 1α–driven immunosuppressive transcription and cAMP-elevating signaling through A2A adenosine receptors (A2ARs) represent a major tumor-protecting pathway that enables immune evasion. Recent promising clinical outcomes due to the blockade of the adenosine-generating enzyme CD73 and A2AR in patients refractory to all other therapies have confirmed the importance of targeting hypoxia-adenosinergic signaling. We report a feasible approach to target the upstream stage of hypoxia-adenosinergic immunosuppression using an oxygen-carrying nanoemulsion (perfluorocarbon blood substitute). We show that oxygenation agent therapy (a) eliminates tumor hypoxia, (b) improves efficacy of endogenously developed and adoptively transferred T cells, and thereby (c) promotes regression of tumors in different anatomical locations. We show that both T cells and NK cells avoid hypoxic tumor areas and that reversal of hypoxia by oxygenation agent therapy increases intratumoral infiltration of activated T cells and NK cells due to reprogramming of the tumor microenvironment (TME). Thus, repurposing oxygenation agents in combination with supplemental oxygen may improve current cancer immunotherapies by preventing hypoxia-adenosinergic suppression, promoting immune cell infiltration and enhancing effector responses. These data also suggest that pretreating patients with oxygenation agent therapy may reprogram the TME from immunosuppressive to immune-permissive prior to adoptive cell therapy, or other forms of immunotherapy.
Authors
Katarina Halpin-Veszeleiova, Michael P. Mallouh, Lucy M. Williamson, Ashley C. Apro, Nuria R. Botticello-Romero, Camille Bahr, Maureen Shin, Kelly M. Ward, Laura Rosenberg, Vladimir B. Ritov, Michail V. Sitkovsky, Edwin K. Jackson, Bruce D. Spiess, Stephen M. Hatfield
Citation Information: JCI Insight. 2025;10(6):e182563. https://doi.org/10.1172/jci.insight.182563.
Abstract
Cancer immunotherapy has emerged as a promising therapeutic modality but heterogeneity in patient responsiveness remains. Thus, greater understanding of the immunologic factors that dictate response to immunotherapy is critical to improve patient outcomes. Here, we show that fibrinogen-like protein 2 (Fgl2) is elevated in the setting of melanoma in humans and mice and plays a functional role in inhibiting the CD8+ T cell response. Surprisingly, the tumor itself is not the major cellular source of Fgl2. Instead, we found that macrophage-secreted Fgl2 dampens the CD8+ T cell response through binding and apoptosis of FcγRIIB+CD8+ T cells. This regulation was CD8+ T cell autonomous and not via an antigen-presenting cell intermediary, as absence of Fcgr2b from the CD8+ T cells rendered T cells insensitive to Fgl2 regulation. Fgl2 is robustly expressed by macrophages in 10 cancer types in humans and in 6 syngeneic tumor models in mice, underscoring the clinical relevance of Fgl2 as a therapeutic target to promote T cell activity and improve patient immunotherapeutic response.
Authors
Kelsey B. Bennion, Julia Miranda R.Bazzano, Danya Liu, Maylene Wagener, Chrystal M. Paulos, Mandy L. Ford
Citation Information: JCI Insight. 2025;10(5):e186409. https://doi.org/10.1172/jci.insight.186409.
Abstract
High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive histological subtype of ovarian cancer and often presents with metastatic disease. The drivers of metastasis in HGSOC remain enigmatic. APOBEC3A (A3A), an enzyme that generates mutations across various cancers, has been proposed as a mediator of tumor heterogeneity and disease progression. However, the role of A3A in HGSOC has not been explored. We observed an association between high levels of APOBEC3-mediated mutagenesis and poor overall survival in primary HGSOC. We experimentally addressed this correlation by modeling A3A expression in HGSOC, and this resulted in increased metastatic behavior of HGSOC cells in culture and distant metastatic spread in vivo, which was dependent on catalytic activity of A3A. A3A activity in both primary and cultured HGSOC cells yielded consistent alterations in expression of epithelial-mesenchymal transition (EMT) genes resulting in hybrid EMT and mesenchymal signatures, providing a mechanism for their increased metastatic potential. Inhibition of key EMT factors TWIST1 and IL-6 resulted in mitigation of A3A-dependent metastatic phenotypes. Our findings define the prevalence of A3A mutagenesis in HGSOC and implicate A3A as a driver of HGSOC metastasis via EMT, underscoring its clinical relevance as a potential prognostic biomarker. Our study lays the groundwork for the development of targeted therapies aimed at mitigating the deleterious effect of A3A-driven EMT in HGSOC.
Authors
Jessica M. Devenport, Thi Tran, Brooke R. Harris, Dylan Fingerman, Rachel A. DeWeerd, Lojain H. Elkhidir, Danielle LaVigne, Katherine Fuh, Lulu Sun, Jeffrey J. Bednarski, Ronny Drapkin, Mary M. Mullen, Abby M. Green
Citation Information: JCI Insight. 2025;10(5):e186344. https://doi.org/10.1172/jci.insight.186344.
Abstract
Glioblastoma (GBM) is the most lethal brain cancer, with GBM stem cells (GSCs) driving therapeutic resistance and recurrence. Targeting GSCs offers a promising strategy for preventing tumor relapse and improving outcomes. We identify SUV39H1, a histone-3, lysine-9 methyltransferase, as critical for GSC maintenance and GBM progression. SUV39H1 is upregulated in GBM compared with normal brain tissues, with single-cell RNA-seq showing its expression predominantly in GSCs due to super-enhancer–mediated activation. Knockdown of SUV39H1 in GSCs impaired their proliferation and stemness. Whole-cell RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. By integrating the RNA-seq data with ATAC-seq data, we further demonstrated that knockdown of SUV39H1 altered chromatin accessibility in key genes associated with these pathways. Chaetocin, an SUV39H1 inhibitor, mimics the effects of SUV39H1 knockdown, reducing GSC stemness and sensitizing cells to temozolomide, a standard GBM chemotherapy. In a patient-derived xenograft model, targeting SUV39H1 inhibits GSC-driven tumor growth. Clinically, high SUV39H1 expression correlates with poor glioma prognosis, supporting its relevance as a therapeutic target. This study identifies SUV39H1 as a crucial regulator of GSC maintenance and a promising therapeutic target to improve GBM treatment and patient outcomes.
Authors
Chunying Li, Qiqi Xie, Sugata Ghosh, Bihui Cao, Yuanning Du, Giau V. Vo, Timothy Y. Huang, Charles Spruck, Richard L. Carpenter, Y. Alan Wang, Q. Richard Lu, Kenneth P. Nephew, Jia Shen
Abstract
Many risk-eligible women refuse tamoxifen for primary prevention of breast cancer due to concerns about common side effects such as vasomotor symptoms. Tamoxifen may also induce or worsen insulin resistance and hypertriglyceridemia, especially in women with obesity. Bazedoxifene/conjugated estrogens (BZA/CE) reduces vasomotor symptoms and is currently undergoing evaluation for breast cancer risk reduction. However, the impact of BZA/CE on insulin resistance and metabolic health, particularly in those with excess adiposity, is understudied. Here, we examined the effects of obesity on response to BZA/CE in a rat model of breast cancer risk using older ovary-intact rats. Female Wistar rats received carcinogen to increase mammary cancer risk and were fed a high-fat diet to promote obesity. Lean and obese rats were selected based on adiposity, then randomized to BZA/CE or vehicle for 8 weeks. BZA/CE reduced adiposity, enriched small (insulin-sensitive) mammary adipocytes, increased the abundance of beneficial metabolic gut microbes (Faecalbaculum rodentium and Odoribacter laneus), and reversed obesity-associated changes in lipids and adipokines. BZA/CE also reversed obesity-induced mammary enrichment of cell proliferation pathways, consistent with risk-reducing effects. Together, these data support the use of BZA/CE to improve metabolic health and reduce breast cancer risk in individuals with obesity.
Authors
Erin D. Giles, Katherine L. Cook, Ramsey M. Jenschke, Karen A. Corleto, Danilo Landrock, Tara N. Mahmood, Katherine E. Sanchez, Alina Levin, Stephen D. Hursting, Bruce F. Kimler, Barry S. Komm, Carol J. Fabian
Abstract
The sentinel lymph node (SLN) is the first lymph node encountered by a metastatic cancer cell and serves as a predictor of poor prognosis, as patients with clinically occult SLN metastases are classified as stage III with elevated rates of recurrence and diminished overall survival. However, the dynamics of immune infiltrates in SLNs remain poorly characterized. Here, using an unbiased Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) technique, we profiled 97,777 cells from SLN tissues obtained from patients with stages I/II and III cutaneous melanoma. We describe the transcriptional programs of a multitude of T, B, and myeloid cell subtypes in SLNs. Based on the proportions of cell types, we determined that SLN subtypes are stratified along a naive → activated axis; patients with a ‘high activated’ signature score appear to be undergoing a robust melanoma antigen-driven adaptive immune response and thus, could be responsive to immunotherapy. Additionally, we identified transcriptomic signatures of SLN-infiltrating dendritic cell subsets that compromise anti-tumor immune responses. Our analyses provide valuable insights into tumor-driven immune changes in the SLN tissue, offering a powerful tool for the informed design of immune therapies for high-risk melanoma patients.
Authors
Eric Engelbrecht, Bryce F. Stamp, Lewis Chew, Omar Sadi Sarkar, Phillip Harter, Sabine J. Waigel, Eric C. Rouchka, Julia H. Chariker, Andrei Smolenkov, Jason A. Chesney, Kelly M. McMasters, Corey T. Watson, Kavitha Yaddanapudi
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