Apolipoprotein E Promotes Immune Suppression in Pancreatic Cancer through NF-κB–Mediated Production of CXCL1

Kemp, Samantha B.; Carpenter, Eileen S.; Steele, Nina G.; Donahue, Katelyn L.; Nwosu, Zeribe C.; Pacheco, Amanda; Velez-Delgado, Ashley; Menjivar, Rosa E.; Lima, Fatima; Espinoza, Carlos; Brown, Kristee; Long, Daniel D.; Lyssiotis, Costas A.; Rao, Arvind; Zhang, Yaqing; Magliano, Marina Pasca di; Crawford, Howard C.

doi:10.1158/0008-5472.can-20-3929

Cited by 113 publications

(80 citation statements)

References 49 publications

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“…We also observed down-regulation of apolipoprotein E ( Apoe ), a secreted protein that our group recently described as highly expressed in TAMs and as promoting immune suppression in invasive pancreatic cancer. 41 In addition, we observed down-regulation of the complement genes C1qa , C1qb , C1qc , and the transcription factor Trem2 , which together define TAMs in several malignancies including, as described by our group, primary and metastatic pancreatic cancer. 42 , 43 These findings are consistent with Kras G12D being required to maintain TAM-like macrophage polarization.…”

Section: Resultssupporting

confidence: 57%

“…After 48–72 hours, we harvested CM from each condition and boiled half of it to denature heat-labile components. CM then was administered to cultured primary mouse fibroblasts (CD1WT and B6318) derived from healthy adult pancreata as previously described 41 , 52 ( Figure 9 A ). Compared with control Dulbecco’s modified Eagle medium (DMEM) media, CM from iKras cells induced expression of Cxcl1 , Il6 , Il33 , and Saa3 in fibroblasts in a Kras G12D -dependent manner ( Figure 9 B ), recapitulating the in vivo results.…”

Section: Resultsmentioning

confidence: 99%

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Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast Reprogramming

Velez-Delgado

Donahue²,

Brown

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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Section: Resultssupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast Reprogramming

Velez-Delgado

Donahue²,

Brown

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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“…Notably, tumor-associated macrophage (TAM) markers such as Arg1 and Ccr1 were downregulated upon Kras* inactivation. We also observed downregulation of Apolipoprotein E (Apoe)a secreted protein that our group recently described as highly expressed in TAMs and as promoting immune suppression in invasive pancreatic cancer (44). Additionally, we observed downregulation of the complement genes C1qa, C1qb, C1qc and the transcription factor Trem2, which together define TAMs in several malignancies (45).…”

Section: Extrinsic Signaling From Kras* Transformed Cells Drives Myeloid Polarizationmentioning

confidence: 55%

Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming

Velez-Delgado

Donahue

Brown

et al. 2021

Preprint

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Oncogenic KRAS is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. While the tumor cell-intrinsic effects of oncogenic Kras expression have been widely studied, its role in regulating the extensive pancreatic tumor microenvironment is less understood. Using a genetically engineered mouse model of inducible and reversible oncogenic Kras expression and a combination of approaches that include mass cytometry and single cell RNA sequencing, we have discovered that non-cell autonomous (i.e., extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, mediating the polarization and function of pro-tumorigenic myeloid cells while also preventing tissue repair. Our study provides fundamental new knowledge on the mechanisms underlying the formation of the fibroinflammatory stroma in pancreatic cancer and highlights stromal pathways with the potential to be exploited therapeutically.

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“…Different CAF subtype clusters are color-coded. Data are from Steele and colleagues [23], and annotations are from Kemp and colleagues [24].…”

Section: Resultsmentioning

confidence: 99%

Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer

Mello

Ngodup

Lee

et al. 2022

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive fibroinflammatory stroma and often experiences conditions of insufficient oxygen availability, or hypoxia. Cancer-associated fibroblasts (CAF) are a predominant and heterogeneous population of stromal cells within the pancreatic tumor microenvironment. Here, we uncover a previously unrecognized role for hypoxia in driving an inflammatory phenotype in PDAC CAFs. We identify hypoxia as a strong inducer of tumor IL1α expression, which is required for inflammatory CAF (iCAF) formation. Notably, iCAFs preferentially reside in hypoxic regions of PDAC. Our data implicate hypoxia as a critical regulator of CAF heterogeneity in PDAC.

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Apolipoprotein E Promotes Immune Suppression in Pancreatic Cancer through NF-κB–Mediated Production of CXCL1

Abstract: Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with few effective therapeutic options. PDA is characterized by an extensive fibroinflammatory stroma that includes abundant

Cited by 113 publications

References 49 publications

Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast Reprogramming

Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast Reprogramming

Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming

Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer

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