Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer

Mello, Ashley M.; Ngodup, Tenzin; Lee, Yusoo; Donahue, Katelyn L.; Li, Jinju; Rao, Arvind; Carpenter, Eileen S.; Crawford, Howard C.; Magliano, Marina Pasca di; Lee, Kyoung Eun

doi:10.1038/s41389-022-00434-2

Cited by 25 publications

(19 citation statements)

References 40 publications

(70 reference statements)

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“…In PDAC and other cancers, including colorectal and head and neck cancers, the evasion of complement cells achieved by elevated CD55 has been shown to confer worse prognosis [50][51][52] . Moreover, hypoxia-inducible factor 1 (HIF1A) expression was spatially associated with iCAF, in line with a recent study suggesting that hypoxia drives iCAF formation in PDAC 53 . Finally, we found a spatial co-localisation of neuropilin-2 (NRP2) with myCAF.…”

Section: Spatial Patterns Of Gene Expression In Pdac Tumour Samplessupporting

confidence: 83%

Transcriptionally defined morphological subtypes of pancreatic ductal adenocarcinoma

Krieger

Sudy

Schicktanz

et al. 2022

Preprint

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Tumour heterogeneity remains a major obstacle to effective and precise therapy for pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer. Several transcriptional subtypes of PDAC with differential prognosis have been described, but they co-occur within tumours and are difficult to distinguish in routine clinical workflows. To investigate the relationship between transcriptional PDAC subtypes, local tissue morphology and the tumour microenvironment, we employed in situ sequencing to profile single cells in their spatial tissue context. We identify five transcriptional subtypes of PDAC cells occurring in three distinct morphological patterns, including secretory tumour cell monolayers, invasive tumour cells with high expression of cell adhesion molecules CEACAM5 and CEACAM6, and spatially distributed tumour cells associated with inflammatory-type fibroblasts. Analysis of bulk RNA-sequencing datasets of the TCGA-PAAD and PACA-AU cohorts according to these spatio-transcriptional subtypes confirmed their prognostic significance. Our results thus indicate an automatable substratification based on spatially-resolved transcriptomics of PDAC and identify distinct subtypes of 'classical' PDAC, representing most cases of this devastating malignancy.

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Section: Spatial Patterns Of Gene Expression In Pdac Tumour Samplessupporting

confidence: 83%

Transcriptionally defined morphological subtypes of pancreatic ductal adenocarcinoma

Krieger

Sudy

Schicktanz

et al. 2022

Preprint

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“…This indicates that CAF subtypes are not static during tumourigenesis but evolve over time. Research has shown that senescent CAFs exhibit a senescence‐associated secretory phenotype (SASP), rich in pro‐inflammatory cytokines, and iCAFs have demonstrated robust performance under hypoxic conditions 74,75 . Given that senescence and hypoxia are prevalent throughout tumour progression, this provides a basis for the evolution of iCAFs.…”

Section: Discussionmentioning

confidence: 99%

The molecular classification of cancer‐associated fibroblasts on a pan‐cancer single‐cell transcriptional atlas

Chen,

Chan,

Xie

et al. 2023

Clinical & Translational Med

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BackgroundCancer‐associated fibroblasts (CAFs), integral to the tumour microenvironment, are pivotal in cancer progression, exhibiting either pro‐tumourigenic or anti‐tumourigenic functions. Their inherent phenotypic and functional diversity allows for the subdivision of CAFs into various subpopulations. While several classification systems have been suggested for different cancer types, a unified molecular classification of CAFs on a single‐cell pan‐cancer scale has yet to be established.MethodsWe employed a comprehensive single‐cell transcriptomic atlas encompassing 12 solid tumour types. Our objective was to establish a novel molecular classification and to elucidate the evolutionary trajectories of CAFs. We investigated the functional profiles of each CAF subtype using Single‐Cell Regulatory Network Inference and Clustering and single‐cell gene set enrichment analysis. The clinical relevance of these subtypes was assessed through survival curve analysis. Concurrently, we employed multiplex immunofluorescence staining on tumour tissues to determine the dynamic changes of CAF subtypes across different tumour stages. Additionally, we identified the small molecule procyanidin C1 (PCC1) as a target for matrix‐producing CAF (matCAF) using molecular docking techniques and further validated these findings through in vitro and in vivo experiments.ResultsIn our investigation of solid tumours, we identified four molecular clusters of CAFs: progenitor CAF (proCAF), inflammatory CAF (iCAF), myofibroblastic CAF (myCAF) and matCAF, each characterised by distinct molecular traits. This classification was consistently applicable across all nine studied solid tumour types. These CAF subtypes displayed unique evolutionary pathways, functional roles and clinical relevance in various solid tumours. Notably, the matCAF subtype was associated with poorer prognoses in several cancer types. The targeting of matCAF using the identified small molecule, PCC1, demonstrated promising antitumour activity.ConclusionsCollectively, the various subtypes of CAFs, particularly matCAF, are crucial in the initiation and progression of cancer. Focusing therapeutic strategies on targeting matCAF in solid tumours holds significant potential for cancer treatment.

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“…147 This also contributes to an immunosuppressive phenotype found in various cell types within the microenvironment, which can hinder the immune system's ability to respond to PDAC effectively. 148 PSCs and myofibroblasts, through increased cytokine production brought on by hypoxia, appear to recruit MDSCs and B cells in PDAC. Soluble MHC class I chain-related gene A (sMICA) plays a crucial role in the impact of hypoxia on immune cells.…”

Section: Targeting Cancer-associated-fibroblast (Caf) In Tme Usingmentioning

confidence: 98%

“…Hypoxia, a well-known component of the solid TME, can aid in tumor survival by inducing hypoxia-regulated mechanisms like NOTCH and c-MET, which promote epithelial-to-mesenchymal transition . This also contributes to an immunosuppressive phenotype found in various cell types within the microenvironment, which can hinder the immune system’s ability to respond to PDAC effectively . PSCs and myofibroblasts, through increased cytokine production brought on by hypoxia, appear to recruit MDSCs and B cells in PDAC.…”

Section: Nanotechnology-based Strategies To Enhance Immunotherapymentioning

confidence: 99%

Advancing Cancer Treatment Through Nanotechnology Driven Immunotherapy for Pancreatic Cancer

Kamalasanan,

et al. 2023

ACS Appl. Nano Mater.

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Pancreatic cancer is expected to be the most lethal cancer by 2030; among that, PDAC is the most prominent one, which is immune resistant, posing substantial hurdles to creating effective therapeutics. Despite the advancements in immunotherapy, its application in PDAC is less successful. Uniquely, PDAC tumors are “cold” to immune response mainly due to suppression of spatiotemporal immune signatures from cells and tumor microenvironment. Contrary to other immune-responsive tumors, immunotherapy in combination with chemotherapy in PDAC, is still diffusion-limiting to the drugs and less cytotoxic to cancer cells. Moreover, newer approaches exploring nanotechnology are being tried to make PDAC “hot” and immunogenic in nature and are promising. This review analyses the design strategies of nanosystems for effective spatiotemporal signaling to improve immune response to PDAC tumors. Particularly, that helps to overcome early evasion in phase I, and resistance to the antitumor immune response by modulating cellular and tumor microenvironment (TME) through the latest advancements in nanotechnology, immune mechanisms, and potential delivery routes for PDAC treatment. Ongoing and completed clinical trials of nanotechnology-driven immunotherapies in pancreatic cancer are also highlighted here. Overall, this approach of nanotechnological strategy to enhance immunotherapy in PDAC holds great promise and may contribute to a groundbreaking shift in the therapeutic management of PDAC and reduce the mortality rate of this lethal disease.

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Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer

Cited by 25 publications

References 40 publications

Transcriptionally defined morphological subtypes of pancreatic ductal adenocarcinoma

Transcriptionally defined morphological subtypes of pancreatic ductal adenocarcinoma

The molecular classification of cancer‐associated fibroblasts on a pan‐cancer single‐cell transcriptional atlas

Advancing Cancer Treatment Through Nanotechnology Driven Immunotherapy for Pancreatic Cancer

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