Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment

García, Carolina J. García; Huang, Yanqing; Fuentes, Natividad R.; Turner, Madeleine; Monberg, Maria E.; Lin, Daniel; Nguyen, Nathalie; Fujimoto, Tara N.; Zhao, Jun; Lee, Jaewon J.; Bernard, Vincent; Yu, Meifang; Delahoussaye, Abagail M.; Sacarello, Iancarlos Jiménez; Caggiano, Emily G.; Phan, J.; Deorukhkar, Amit; Molkentine, Jessica M.; Saur, Dieter; Maitra, Anirban; Taniguchi, Cullen M.

doi:10.1053/j.gastro.2022.02.024

Cited by 74 publications

(46 citation statements)

References 47 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While our data indicate a major role of HIF-1α in the hypoxia-induced inflammatory response, we cannot exclude involvement of HIF-2α in this process. HIF-2α but not HIF-1α expression in αSMA + CAFs has been shown to accelerate PDAC progression by establishing an immunosuppressive TME (47).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines

Schwörer

Ros

Tsanov

et al. 2022

Preprint

View full text Add to dashboard Cite

Cancer-associated fibroblasts (CAFs) are a major cell type in the stroma of solid tumors and can exert both tumor-promoting and tumor-restraining functions. This functional heterogeneity is correlated with the existence of transcriptionally distinct subpopulations of CAFs. CAF heterogeneity is observed in pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by a remarkably dense and hypoxic stroma that features tumor-restraining myofibroblastic CAFs (myCAFs) and tumor-supporting inflammatory CAFs (iCAFs). While CAF heterogeneity can be driven in part by tumor cell-produced cytokines, other determinants shaping CAF identity and function are largely unknown. In vivo, we found that iCAFs display a hypoxic gene expression and biochemical profile and are enriched in hypoxic regions of PDAC tumors. Hypoxia leads fibroblasts to acquire an inflammatory gene expression signature and synergizes with cancer cell-derived cytokines to promote an iCAF phenotype in a HIF-1α dependent fashion. Furthermore, we show that HIF-1α stabilization is sufficient to induce an iCAF phenotype in stromal cells introduced into PDAC organoid co-cultures and to promote PDAC tumor growth. These findings indicate hypoxia-induced HIF-1α as a regulator of CAF heterogeneity and promoter of tumor progression in PDAC.

show abstract

Section: Discussionmentioning

confidence: 99%

Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines

Schwörer

Ros

Tsanov

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Besides that, specific HIF-2 inhibitors, such as belzutifan, are already designed and in an advanced phase of testing in renal cell carcinoma, with promising activity [ 31 ]. Stromal HIF-2 exerts an immune suppressive role in other tumor types as well, for example, pancreatic adenocarcinoma [ 32 ]. By revealing a network of genes-players that are involved in this process in direct association with HIF-2 in UC, this study provides several insights for deepening our understanding of the mechanistic processes that are potentially involved.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Inducible Factor-2-Altered Urothelial Carcinoma: Clinical and Genomic Features

et al. 2022

View full text Add to dashboard Cite

Background: Hypoxia is recognized as a key feature of cancer growth and is involved in various cellular processes, including proliferation, angiogenesis, and immune surveillance. Besides hypoxia-inducible factor 1-alpha (HIF-1α), which is the main mediator of hypoxia effects and can also be activated under normoxic conditions, little is known about its counterpart, HIF-2. This study focused on investigating the clinical and molecular landscape of HIF-2-altered urothelial carcinoma (UC). Methods: Publicly available next-generation sequencing (NGS) data from muscle-invasive UC cell lines and patient tumor samples from the MSK/TCGA 2020 cohort (n = 476) were interrogated for the level of expression (mRNA, protein) and presence of mutations, copy number variations, structural variants in the EPAS1 gene encoding HIF-2, and findings among various clinical (stage, grade, progression-free and overall survival) and molecular (tumor mutational burden, enriched gene expression) parameters were compared between altered and unaltered tumors. Results: 19% (7/37) of UC cell lines and 7% (27/380) of patients with muscle-invasive UC display high EPAS1 mRNA and protein expression or/and EPAS1 alterations. EPAS1-altered tumors are associated with higher stage, grade, and lymph node metastasis as well as with shorter PFS (14 vs. 51 months, q = 0.01) and OS (15 vs. 55 months, q = 0.01). EPAS1 mRNA expression is directly correlated with that of its target-genes, including VEGF, FLT1, KDR, DLL4, CDH5, ANGPT1 (q < 0.001). While there is a slightly higher tumor mutational burden in EPAS1-altered tumors (9.9 vs. 4.9 mut/Mb), they are enriched in and associated with genes promoting immune evasion, including ARID5B, SPINT1, AAK1, CLIC3, SORT1, SASH1, and FGFR3, respectively (q < 0.001). Conclusions: HIF-2-altered UC has an aggressive clinical and a distinct genomic and immunogenomic profile enriched in angiogenesis- and immune evasion-preventing genes.

show abstract

“…This duality may reflect the effect of other nearby cells, which ongoing multidimensional spatial studies aim to determine. Hypoxia-inducible factor-2α (HIF2α) production by fibroblasts in the relatively hypoxic stroma of PDAC also promotes M2 macrophage polarization, as evidenced by a recent mouse study [ 29 ]. In contrast, macrophages also express colony stimulating factor 1 receptor (CSF-1R) and focal adhesion kinase (FAK) that mediate signaling cascades to promote MDSC, TAM, and Treg infiltration and are under investigation as therapeutic targets for the treatment of PDAC [ 30 ].…”

Section: Myeloid Compartmentmentioning

confidence: 99%

The Tumor Immune Microenvironment in Pancreatic Ductal Adenocarcinoma: Neither Hot nor Cold

Rubin

Sojwal

Gubatan

et al. 2022

Cancers

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic tumor and is associated with poor prognosis and treatment response. The tumor microenvironment (TME) is recognized as an important factor in metastatic progression across cancers. Despite extensive study of the TME in PDAC, the cellular and molecular signaling networks remain poorly understood, largely due to the tremendous heterogeneity across tumors. While earlier work characterized PDAC as an immunologically privileged tumor poorly recognized by the immune system, recent studies revealed the important and nuanced roles of immune cells in the pathogenesis of PDAC. Distinct lymphoid, myeloid, and stromal cell types in the TME exert opposing influences on PDAC tumor trajectory, suggesting a more complex organization than the classical “hot” versus “cold” tumor distinction. We review the pro- and antitumor immune processes found in PDAC and briefly discuss their leverage for the development of novel therapeutic approaches in the field.

show abstract

Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment

Cited by 74 publications

References 47 publications

Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines

Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines

Hypoxia-Inducible Factor-2-Altered Urothelial Carcinoma: Clinical and Genomic Features

The Tumor Immune Microenvironment in Pancreatic Ductal Adenocarcinoma: Neither Hot nor Cold

Contact Info

Product

Resources

About