A Novel Pancreatic Cancer Hypoxia Status Related Gene Signature for Prognosis and Therapeutic Responses

Ren, Min; Zhang, Jianing; Zong, Rongrong; Sun, Hongguang

doi:10.1007/s12033-023-00807-x

Cited by 4 publications

(5 citation statements)

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“…utilized a compact 15 gene version of Buffa signature to derive a 6 gene risk score in PDAC ( 22 ). It is pertinent to note that all published hypoxia gene signatures and risk scores have been shown to be correlated with poor prognosis in PDAC ( 15 , 22 ). In multiple published reports, patients were classified as high or low based on a median expression cut-off ( 22 – 24 ).…”

Section: Discussionmentioning

confidence: 99%

“…It is pertinent to note that all published hypoxia gene signatures and risk scores have been shown to be correlated with poor prognosis in PDAC ( 15 , 22 ). In multiple published reports, patients were classified as high or low based on a median expression cut-off ( 22 – 24 ). In our study, we sought to compare cases with notable differences in hypoxia status, and therefore used a cut-off of top versus bottom quartiles of expression for our hypoxia score, an approach that is used to classify patients in certain gene expression profiling studies ( 68 , 69 ).…”

Section: Discussionmentioning

confidence: 99%

“…As such, in published reports on hypoxia, cases are either stratified by the expression levels of a hypoxia gene signature or by a hypoxia risk score, where the expression of hypoxia-linked genes (selected for the score through survival regression analyses) is multiplied by their regression coefficients (15). In the past few months, another report by Ren et al utilized a compact 15 gene version of Buffa signature to derive a 6 gene risk score in PDAC (22). It is pertinent to note that all published hypoxia gene signatures and risk scores have been shown to be correlated with poor prognosis in PDAC (15,22).…”

Section: Discussionmentioning

confidence: 99%

“…In the past few months, another report by Ren et al utilized a compact 15 gene version of Buffa signature to derive a 6 gene risk score in PDAC (22). It is pertinent to note that all published hypoxia gene signatures and risk scores have been shown to be correlated with poor prognosis in PDAC (15,22). In multiple published reports, patients were classified as high or low based on a median expression cut-off (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

“…However, further studies are warranted to dissect the immune landscape of hypoxic pancreatic adenocarcinomas. Recently, gene signatures for hypoxia have been used to study patient outcomes and characterize the TME using transcriptomics data from a number of cancers including gastric cancer (20), bladder cancer (21), and PDAC (22)(23)(24). One of the most widely utilized gene signatures for hypoxia is a 51-gene score developed Buffa et al (25).…”

Section: Introductionmentioning

confidence: 99%

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High hypoxia status in pancreatic cancer is associated with multiple hallmarks of an immunosuppressive tumor microenvironment

Sadozai,

Acharjee,

Kayani

et al. 2024

Front. Immunol.

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IntroductionPancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is a particularly lethal disease that is often diagnosed late and is refractory to most forms of treatment. Tumour hypoxia is a key hallmark of PDAC and is purported to contribute to multiple facets of disease progression such as treatment resistance, increased invasiveness, metabolic reprogramming, and immunosuppression.MethodsWe used the Buffa gene signature as a hypoxia score to profile transcriptomics datasets from PDAC cases. We performed cell-type deconvolution and gene expression profiling approaches to compare the immunological phenotypes of cases with low and high hypoxia scores. We further supported our findings by qPCR analyses in PDAC cell lines cultured in hypoxic conditions.ResultsFirst, we demonstrated that this hypoxia score is associated with increased tumour grade and reduced survival suggesting that this score is correlated to disease progression. Subsequently, we compared the immune phenotypes of cases with high versus low hypoxia score expression (HypoxiaHI vs. HypoxiaLOW) to show that high hypoxia is associated with reduced levels of T cells, NK cells and dendritic cells (DC), including the crucial cDC1 subset. Concomitantly, immune-related gene expression profiling revealed that compared to HypoxiaLOW tumours, mRNA levels for multiple immunosuppressive molecules were notably elevated in HypoxiaHI cases. Using a Random Forest machine learning approach for variable selection, we identified LGALS3 (Galectin-3) as the top gene associated with high hypoxia status and confirmed its expression in hypoxic PDAC cell lines.DiscussionIn summary, we demonstrated novel associations between hypoxia and multiple immunosuppressive mediators in PDAC, highlighting avenues for improving PDAC immunotherapy by targeting these immune molecules in combination with hypoxia-targeted drugs.

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