GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer

O’Kane, Grainne M.; Grünwald, Barbara; Jang, Gun-Ho; Masoomian, Mehdi; Picardo, Sarah; Grant, Robert C.; Denroche, Robert E.; Zhang, Amy; Wang, Yifan; Lam, Bernard; Krzyzanowski, Paul M.; Lungu, Illinca M.; Bartlett, John M.S.; Peralta, Melanie; Vyas, Foram; Khokha, Rama; Biagi, James; Chadwick, Dianne; Ramotar, Stephanie; Hutchinson, Shawn; Dodd, Anna; Wilson, Julie M.; Notta, Faiyaz; Zogopoulos, George; Gallinger, Steven; Knox, Jennifer J.; Fischer, Sandra E.

doi:10.1158/1078-0432.ccr-19-3724

Cited by 207 publications

(210 citation statements)

References 34 publications

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“…[2][3][4][5][6] In PDAC, bulk transcriptional profiling has defined two major transcriptional subtypes, basal-like/squamous (hereafter referred to as "basal") and classical, where the former is associated with worse prognosis and greater treatment resistance. [3][4][5][7][8][9][10][11][12][13][14] However, classification based on bulk expression profiling can obscure clinically relevant cellular attributes because it reduces signals from multiple cell types to a single, whole sample average. In reality, PDAC tumors, like many other cancers, are complex multicellular ecosystems shaped by both malignant and microenvironmental features.…”

Section: Mainmentioning

confidence: 99%

The tumor microenvironment drives transcriptional phenotypes and their plasticity in metastatic pancreatic cancer

Raghavan

Winter

Navia

et al. 2020

Preprint

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In pancreatic ductal adenocarcinoma (PDAC), the basal-like and classical transcriptional subtypes are associated with differential chemotherapy sensitivity and patient survival. These phenotypes have been defined using bulk transcriptional profiling, which can mask underlying cellular heterogeneity and the biologic mechanisms that distinguish these subtypes. Furthermore, few studies have interrogated metastases, which are the cause of mortality in most patients with this highly lethal disease. Using single-cell RNA-sequencing of metastatic needle biopsies and matched organoid models, we demonstrate intra-tumoral subtype heterogeneity at the single-cell level and define a continuum for the basal-like and classical phenotypes that includes hybrid cells that co-express features of both states. Basal-like tumors show enrichment of mesenchymal and stem-like programs, and demonstrate immune exclusion and tumor cell crosstalk with specific macrophage subsets. Conversely, classical tumors harbor greater immune infiltration and a relatively pro-angiogenic microenvironment. Matched organoid models exhibit a strong bias against the growth of basal-like cells in standard organoid media, but modification of culture conditions can rescue the basal-like phenotype. This study reframes the transcriptional taxonomy of PDAC, demonstrates how divergent transcriptional subtypes associate with unique tumor microenvironments, and highlights the importance of evaluating both genotype and transcriptional phenotype to establish high-fidelity patient-derived cancer models.

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Section: Mainmentioning

confidence: 99%

The tumor microenvironment drives transcriptional phenotypes and their plasticity in metastatic pancreatic cancer

Raghavan

Winter

Navia

et al. 2020

Preprint

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“…RNA sequencing data was obtained from patients on the COMPASS trial, as described previously (59). Briefly, biopsies from the primary or metastatic site were collected prior to start of any treatment in a prospective multi-institutional Canadian cohort study.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, biopsies from the primary or metastatic site were collected prior to start of any treatment in a prospective multi-institutional Canadian cohort study. Frozen specimens underwent laser capture microdissection for enrichment of tumor, and Transcript per million (TPM) RNA sequencing data were analyzed as described (59). Modified Moffit subtypes and RNA expression was dichotomized using the maximal chi-squared statistics as described (59).…”

Section: Methodsmentioning

confidence: 99%

NOX4 links metabolic regulation in pancreatic cancer to endoplasmic reticulum redox vulnerability and dependence on PRDX4

Jain

Dvorkin‐Gheva

Mollen

et al. 2020

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is an almost universally fatal malignancy and there is an urgent need for new therapeutic targets. PDAC cells harbor genetic alterations and display metabolic changes that render them vulnerable to perturbations in redox homeostasis. Peroxiredoxin 4 (PRDX4) supports redox homeostasis by metabolizing H2O2 in the endoplasmic reticulum (ER). Based on functional genomics, we found that PDAC cell lines are dependent on PRDX4 for their growth and survival. We validated this dependency in established and primary PDAC cells, as well as 3D models and orthotopic xenografts. Cell death induced by PRDX4 depletion was accompanied by increased levels of reactive oxygen species (ROS), DNA damage and a DNA-PKcs-governed DNA damage response. As such, PRDX4 depletion also sensitized cells and tumors to ionizing radiation. The source of ROS that created a dependency on PRDX4 was attributed to NADPH oxidase 4 (NOX4), which localizes to the ER membrane. The functional requirement for PRDX4 was correlated with cellular NADPH levels across different models of PDAC and could be rescued by depletion of NOX4 or NADPH. As such, this study has identified NOX4 as a link between metabolic deregulation and ER-specific redox vulnerability in PDAC. Since PRDX4 is not an essential gene in normal tissues, our work also suggests that PRDX4 represents a novel therapeutic target for pancreatic cancer that may be particularly potent in combination with radiotherapy.

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“…The same research group has very recently confirmed within the COMPASS trial [63] the role of GATA6 expression as a simple surrogate biomarker to define "classical" transcriptomic type, as well as the very high chemo-resistance nature of basal-like tumors [64]. Indeed, basal-like tumors treated with mFOLFIRINOX showed a higher progression rate (60%) compared to that of Classical PDACs (15%), p = 0.0002, suggesting once more that perhaps mFOLFIRINOX should not be the right chemotherapy regimen for Basal-like cancers.…”

Section: Single-cell Analysis Reveals the Cellular Ecosystem Of Pdacmentioning

confidence: 99%

“…In fact, preliminary evidences suggest that classic-type PDACs respond to mFOLFIRINOX in advanced stage [43,64], as well as they seem to receive benefit from adjuvant 5-FU if resected [45], while basal-like tumors (mainly basal-like A) are highly resistant to 5-FU based chemotherapy regimens, and we should consider an alternative drug combination (like a gemcitabine-based one). However, even if we use from the beginning the suggested right regimen for a specific tumor type, "subtype-switch" unavoidably could occur and could be responsible for the disease progression.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Pancreatic Cancer Molecular Classifications: From Bulk Genomics to Single Cell Analysis

Pompella

Tirino

Pappalardo

et al. 2020

IJMS

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Pancreatic cancer represents one of the most lethal disease worldwide but still orphan of a molecularly driven therapeutic approach, although many genomic and transcriptomic classifications have been proposed over the years. Clinical heterogeneity is a hallmark of this disease, as different patients show different responses to the same therapeutic regimens. However, genomic analyses revealed quite a homogeneous disease picture, with very common mutations in four genes only (KRAS, TP53, CDKN2A, and SMAD4) and a long tail of other mutated genes, with doubtful pathogenic meaning. Even bulk transcriptomic classifications could not resolve this great heterogeneity, as many informations related to small cell populations within cancer tissue could be lost. At the same time, single cell analysis has emerged as a powerful tool to dissect intratumoral heterogeneity like never before, with possibility of generating a new disease taxonomy at unprecedented molecular resolution. In this review, we summarize the most relevant genomic, bulk and single-cell transcriptomic classifications of pancreatic cancer, and try to understand how novel technologies, like single cell analysis, could lead to novel therapeutic strategies for this highly lethal disease.

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GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer

Abstract: S 2020, 'GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer. ', Clinical Cancer Research.

Cited by 207 publications

References 34 publications

The tumor microenvironment drives transcriptional phenotypes and their plasticity in metastatic pancreatic cancer

The tumor microenvironment drives transcriptional phenotypes and their plasticity in metastatic pancreatic cancer

NOX4 links metabolic regulation in pancreatic cancer to endoplasmic reticulum redox vulnerability and dependence on PRDX4

Pancreatic Cancer Molecular Classifications: From Bulk Genomics to Single Cell Analysis

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