Loss of PBRM1 accelerates pancreatic cancer progression by inducing acquisition of mesenchymal phenotype and inflammatory cancer-associated fibroblasts reprogramming.
Aug 2026· Cancer Letters· pp.
218797
· 0 citations· 39 references
Medicine
TL;DR
Findings indicated a tumor-suppressing role of PBRM1 in PDAC, which constitutes a specific subgroup of patients with aggressive phenotype and prognostic significance.
Abstract
Background
PBRM1 is an important subunit of the SWI/SNF complex, which broadly regulates gene transcription by chromatin remodeling. Genomic alterations of PBRM1 have been found in patients with pancreatic ductal adenocarcinoma (PDAC), but its molecular functions remain unclear.
Methods
Clinical relevance of PBRM1 was analyzed by using human PDAC samples and public genomic datasets. Mice with concomitant pancreas-specific Pbrm1 deletion in Kras-driven genetic PDAC models were generated. Single-cell transcriptomics were performed to determine tumor phenotype and microenvironment reprogramming.
Results
Reduction of PBRM1 expression was observed in human PDAC tissues and correlated with poor prognosis and metastasis. Pbrm1 loss promoted ductal metaplasia and delayed epithelial recovery in mice with caerulein-induced pancreatic injury. In PDAC model with either mutant Kras alone or in combination with Trp53 mutation, lack of Pbrm1 markedly accelerated tumor development and progression. Bulk transcriptomics and scRNA-seq identified reprogramming of both tumor compartment with mesenchymal phenotype acquisition and stroma compartment with inflammatory cancer-associated fibroblasts (iCAFs) transformation. Mechanistically, Pbrm1 deletion induced Zeb1 upregulation through epigenetic chromatin remodeling, thereby enhancing epithelial-mesenchymal and basal-like subtype transition.
Conclusions
These findings indicated a tumor-suppressing role of PBRM1 in PDAC. PBRM1-deficient PDAC constitutes a specific subgroup of patients with aggressive phenotype and prognostic significance.
KMT2D (known as Mll4 in mice) is a histone methyltransferase and a critical epigenetic regulator frequently mutated across a range of cancers. TCGA data indicate alterations in KMT2D, including mutations and changes in expression, in approximately 11% of pancreatic cancer patients. Our previous research showed that KMT2D loss in human pancreatic cancer cells induces epithelial-to-mesenchymal transition (EMT), promoting aggressive disease progression. We hypothesized that KMT2D loss not only drives intrinsic tumor changes but also remodels the immune microenvironment.
We performed bulk RNA sequencing on Mll4 knockdown mouse pancreatic cancer cells (KPC7940) and proteomic profiling of their conditioned media to identify changes in secreted proteins. Pathway analysis focused on TNF-alpha/NF-kB, IL-6/JAK/STAT3, and IL-2/STAT5 signaling. A pancreas-specific Mll4 knockout model (KPCM: KrasG12D/+; Trp53R172H/+; Ptf1a-Cre; Mll4SETflox/flox) was generated to assess tumor progression in vivo. Tumor proliferation was evaluated by Ki-67 immunohistochemistry. Single-cell RNA sequencing was used to characterize the immune microenvironment in KPC and KPCM tumors.
KPCM mice developed pancreatic cancer by 3 weeks compared to 16—20 weeks in KPC controls, with median survival of 24 vs 126.5 days. Ki-67 staining confirmed higher proliferation in KPCM tumors. Bulk RNA-seq and proteomic analysis revealed altered expression of secreted proteins enriched in inflammatory and immunomodulatory pathways. Single-cell RNA sequencing showed increased myeloid populations and NK/T cells expressing immunosuppressive markers, including CTLA4, CD274, and PDCD1, in KPCM tumors.
KMT2D plays a pivotal role in orchestrating both tumor-intrinsic and microenvironmental processes that drive pancreatic cancer progression. Understanding how KMT2D loss reprograms the immune landscape may uncover novel immunomodulatory therapeutic targets for pancreatic cancer.
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Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
H. Acosta-Vilanova, H. Kim, Shungang Zhang et al.· Journal of Immunology· 0 citations
Breast cancer remains a primary cause of cancer-associated death globally, largely due to distant metastasis and therapeutic resistance. While matrix remodeling associated 5 (MXRA5) has been implicated in inflammation and fibrosis, its specific biological function and mechanistic role in breast cancer progression remain unclear. Herein, multi-omics analysis and in vitro functional assays were employed to investigate the expression pattern, clinical significance, and biological function of MXRA5 within breast cancer. We observed that MXRA5 was considerably upregulated within breast cancer tissues in comparison with normal controls at both mRNA and protein levels. Crucially, elevated MXRA5 expression exhibited a positive correlation with advanced lymph node metastasis and impaired clinical prognosis, including overall survival, disease-specific survival, and progression-free interval, particularly within the Luminal B and HER2+ subtypes. Functional validation demonstrated that MXRA5 silencing markedly repressed the abilities of BT474 and MDA-MB-361 cells to proliferate, to migrate, and to invade in vitro, and significantly reduced lung metastasis in vivo. Mechanistically, bioinformatics analysis and pharmacological rescue experiments demonstrated that MXRA5 promotes tumor aggressiveness by activating the PI3K/AKT/mTOR signaling axis, which subsequently drives the epithelial-to-mesenchymal transition (EMT) pathway, evidenced by the positive regulation of key EMT transcription factors Snail and Twist, as well as the mesenchymal marker Vimentin. Collectively, these findings identify MXRA5 as a novel oncogenic driver in breast carcinoma and reveal its potential as a valuable prognostic biomarker and therapeutic target for managing metastatic disease.
Jian Wang, Jie Tang, Yaoxin Wang· Korean Journal of Physiology...· 0 citations
Background Pancreatic ductal adenocarcinoma (PAAD) is a highly lethal malignancy characterized by metabolic remodeling and an immunosuppressive tumor microenvironment. Hematopoietic prostaglandin D synthase (HPGDS), a key enzyme involved in prostaglandin and lipid-associated inflammatory signaling, remains insufficiently characterized in PAAD. Methods We integrated public transcriptomic datasets, survival cohorts, immunotherapy-related datasets, single-cell RNA sequencing data, and in vitro validation assays to evaluate the expression pattern, clinical relevance, immune association, and functional role of HPGDS in pancreatic cancer. Results HPGDS was upregulated in pancreatic cancer tissues and cell lines and was associated with clinicopathological progression and unfavorable prognosis. HPGDS expression correlated with immune checkpoint molecules, immune cell infiltration, chemokine receptor networks, and cell-cell communication programs within the pancreatic tumor microenvironment. In public immunotherapy cohorts, higher HPGDS expression was associated with poorer response to immune checkpoint blockade, although the predictive performance varied across cohorts. Pharmacological inhibition and shRNA-mediated knockdown supported a role for HPGDS in pancreatic cancer cell proliferation, whereas effects on migration and invasion were less consistent between inhibitor-based and genetic approaches. Conclusion These findings suggest that HPGDS is associated with prognosis and immune microenvironment remodeling in pancreatic cancer and may represent a candidate biomarker for further translational investigation. Because many findings are based on retrospective public datasets and correlation analyses, additional mechanistic, in vivo, and clinical validation studies are required.
Hao Ye, Minjuan Du, Chenjun Xie et al.· Cancer Management and Resear...· 0 citations
A GSTT1HighCD133High stem-like subpopulation in metastatic PDA is identified and an FGFR-dependent signaling axis that sustains this state is identified, representing a potential therapeutic vulnerability.
D. de la Caridad Delgado Herrera, Alejandro Arroyo Roman, Riyan N. Campbell et al.· Cancer Letters· 0 citations
CD73 is an enzyme that generates extracellular adenosine and has been implicated in tumor-associated immune suppression, but its biological and clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains incompletely understood. We investigated the prognostic relevance and biological functions of CD73 in PDAC using transcriptomic analyses, in vitro functional assays, and in vivo mouse models. Transcriptomic analyses consistently showed that CD73 expression was correlated with hypoxia, glycolysis related, and cell-cycle programs. In agreement with these findings, hypoxic exposure induced CD73 mRNA expression in a subset of PDAC cell lines, and CD73 knockdown modestly affected glycolysis related extracellular acidification (ECAR) in a cell line dependent manner, and modulation of CD73 expression altered PDAC cell growth. CD73 expression was also associated with reduced intratumoral CD8+ T cell infiltration and cytolytic activity in human PDAC cohorts. In vivo, CD73 overexpression accelerated cancer progression and shortened survival in immunocompetent mice, whereas this effect was abrogated in immunodeficient NSG mice. Flow cytometric analysis further demonstrated reduced intratumoral CD8+ T cell infiltration in CD73 overexpressing tumors. Clinically, high CD73 expression was consistently associated with worse survival in multiple PDAC cohorts. Collectively, these findings suggest that CD73 is associated with multiple features of PDAC progression, including hypoxia-related metabolic programs, tumor growth, and suppression of anti-tumor immunity. CD73 may therefore represent a biologically relevant biomarker and a potential therapeutic target in PDAC.
Eriko Katsuta, Aarohan M Burma, Eito Nakagawa et al.· Frontiers in Immunology· 0 citations
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide, characterized by late diagnosis, rapid progression and resistance to conventional therapies. Cancer-associated fibroblast (CAF)-derived extracellular vesicles (EVs) contribute to PDAC progression, but their downstream molecular effectors remain unclear. In the present study, it was demonstrated that CAF-derived EVs enhanced the proliferative, migratory and invasive capacity of PDAC cells across two independent cell lines, as assessed by Cell Counting Kit-8 assays and Transwell migration and Matrigel invasion assays. RAP1B was identified as a prominently upregulated protein by label-free proteomic profiling following EV exposure. High RAP1B expression, evaluated by immunohistochemistry, in a cohort of 77 resected PDAC specimens tended to be more frequent with advancing pathological stage and was associated with poorer overall survival. RAP1B knockdown using small interfering RNA suppressed proliferation and motility in PDAC cells and induced cytokinesis failure characterized by multinucleation and cytoskeletal abnormalities, as demonstrated by time-lapse imaging and immunofluorescence staining. Proteomic profiling of RAP1B-knockdown cells identified anillin (ANLN) as a downstream mediator; ANLN knockdown recapitulated these cytokinetic defects, whereas ANLN knockdown did not reciprocally affect RAP1B levels, establishing a unidirectional RAP1B/ANLN axis. Furthermore, RAP1B depletion sensitized PDAC cells to gemcitabine, showing additive growth inhibition. In conclusion, CAF-derived EVs mediate PDAC progression via the RAP1B/ANLN axis, representing a novel and promising therapeutic target in PDAC.
Daigo Yoshimori, M. Kudo, Kousuke Ishino et al.· Oncology Report· 0 citations