Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast ReprogrammingSummary
Background & Aims: Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. Although the tumor cell–intrinsic effects of oncogenic Kras expression have been widely studi...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X22000431 |
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| author | Ashley Velez-Delgado Katelyn L. Donahue Kristee L. Brown Wenting Du Valerie Irizarry-Negron Rosa E. Menjivar Emily L. Lasse Opsahl Nina G. Steele Stephanie The Jenny Lazarus Veerin R. Sirihorachai Wei Yan Samantha B. Kemp Samuel A. Kerk Murali Bollampally Sion Yang Michael K. Scales Faith R. Avritt Fatima Lima Costas A. Lyssiotis Arvind Rao Howard C. Crawford Filip Bednar Timothy L. Frankel Benjamin L. Allen Yaqing Zhang Marina Pasca di Magliano |
| author_facet | Ashley Velez-Delgado Katelyn L. Donahue Kristee L. Brown Wenting Du Valerie Irizarry-Negron Rosa E. Menjivar Emily L. Lasse Opsahl Nina G. Steele Stephanie The Jenny Lazarus Veerin R. Sirihorachai Wei Yan Samantha B. Kemp Samuel A. Kerk Murali Bollampally Sion Yang Michael K. Scales Faith R. Avritt Fatima Lima Costas A. Lyssiotis Arvind Rao Howard C. Crawford Filip Bednar Timothy L. Frankel Benjamin L. Allen Yaqing Zhang Marina Pasca di Magliano |
| author_sort | Ashley Velez-Delgado |
| collection | DOAJ |
| description | Background & Aims: Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. Although 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. Methods: 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 studied the effect of oncogenic KRAS in the tumor microenvironment. Results: We have discovered that non–cell autonomous (ie, extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, and the main source of cytokines mediating the polarization of protumorigenic macrophages while also preventing tissue repair. Conclusions: Our study provides fundamental 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. |
| first_indexed | 2024-04-12T16:31:42Z |
| format | Article |
| id | doaj.art-20125fcc27cc45cf89b627da102ba12b |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-04-12T16:31:42Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-20125fcc27cc45cf89b627da102ba12b2022-12-22T03:25:07ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2022-01-0113616731699Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast ReprogrammingSummaryAshley Velez-Delgado0Katelyn L. Donahue1Kristee L. Brown2Wenting Du3Valerie Irizarry-Negron4Rosa E. Menjivar5Emily L. Lasse Opsahl6Nina G. Steele7Stephanie The8Jenny Lazarus9Veerin R. Sirihorachai10Wei Yan11Samantha B. Kemp12Samuel A. Kerk13Murali Bollampally14Sion Yang15Michael K. Scales16Faith R. Avritt17Fatima Lima18Costas A. Lyssiotis19Arvind Rao20Howard C. Crawford21Filip Bednar22Timothy L. Frankel23Benjamin L. Allen24Yaqing Zhang25Marina Pasca di Magliano26Department of Cell and Developmental Biology, Ann Arbor, MichiganCancer Biology Program, Ann Arbor, MichiganDepartment of Surgery, Ann Arbor, MichiganDepartment of Surgery, Ann Arbor, MichiganDepartment of Surgery, Ann Arbor, MichiganCellular and Molecular Biology Program, Ann Arbor, MichiganCancer Biology Program, Ann Arbor, MichiganDepartment of Cell and Developmental Biology, Ann Arbor, MichiganDepartment of Computational Medicine and Bioinformatics, Ann Arbor, MichiganDepartment of Surgery, Ann Arbor, MichiganCancer Biology Program, Ann Arbor, MichiganDepartment of Surgery, Ann Arbor, MichiganMolecular and Cellular Pathology Program, Ann Arbor, MichiganCancer Biology Program, Ann Arbor, MichiganLife Sciences and Arts College, Ann Arbor, MichiganLife Sciences and Arts College, Ann Arbor, MichiganDepartment of Cell and Developmental Biology, Ann Arbor, MichiganLife Sciences and Arts College, Ann Arbor, MichiganDepartment of Surgery, Ann Arbor, MichiganCancer Biology Program, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, Michigan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, MichiganCancer Biology Program, Ann Arbor, Michigan; Department of Computational Medicine and Bioinformatics, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, Michigan; Michigan Institute of Data Science, Ann Arbor, Michigan; Department of Radiation Oncology, University of Michigan, Ann Arbor, MichiganCancer Biology Program, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, Michigan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, MichiganDepartment of Surgery, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, MichiganDepartment of Surgery, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, MichiganDepartment of Cell and Developmental Biology, Ann Arbor, MichiganDepartment of Surgery, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, Michigan; Yaqing Zhang, MB; PhD, Rogel Cancer Center, Room 6110, 1500 E Medical Center Drive, Ann Arbor, Michigan 48109. fax: (734) 647-9271.Department of Cell and Developmental Biology, Ann Arbor, Michigan; Cancer Biology Program, Ann Arbor, Michigan; Department of Surgery, Ann Arbor, Michigan; Cellular and Molecular Biology Program, Ann Arbor, Michigan; Rogel Cancer Center, Ann Arbor, Michigan; Correspondence Address correspondence to: Marina Pasca di Magliano, PhD, Rogel Cancer Center, Room 6306, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109. fax: (734) 647-9271.Background & Aims: Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. Although 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. Methods: 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 studied the effect of oncogenic KRAS in the tumor microenvironment. Results: We have discovered that non–cell autonomous (ie, extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, and the main source of cytokines mediating the polarization of protumorigenic macrophages while also preventing tissue repair. Conclusions: Our study provides fundamental 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.http://www.sciencedirect.com/science/article/pii/S2352345X22000431Pancreatic CancerTransformationFibroblastsMacrophages |
| spellingShingle | Ashley Velez-Delgado Katelyn L. Donahue Kristee L. Brown Wenting Du Valerie Irizarry-Negron Rosa E. Menjivar Emily L. Lasse Opsahl Nina G. Steele Stephanie The Jenny Lazarus Veerin R. Sirihorachai Wei Yan Samantha B. Kemp Samuel A. Kerk Murali Bollampally Sion Yang Michael K. Scales Faith R. Avritt Fatima Lima Costas A. Lyssiotis Arvind Rao Howard C. Crawford Filip Bednar Timothy L. Frankel Benjamin L. Allen Yaqing Zhang Marina Pasca di Magliano Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast ReprogrammingSummary Cellular and Molecular Gastroenterology and Hepatology Pancreatic Cancer Transformation Fibroblasts Macrophages |
| title | Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast ReprogrammingSummary |
| title_full | Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast ReprogrammingSummary |
| title_fullStr | Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast ReprogrammingSummary |
| title_full_unstemmed | Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast ReprogrammingSummary |
| title_short | Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast ReprogrammingSummary |
| title_sort | extrinsic kras signaling shapes the pancreatic microenvironment through fibroblast reprogrammingsummary |
| topic | Pancreatic Cancer Transformation Fibroblasts Macrophages |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X22000431 |
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