Research ArticleOncology Open Access | 10.1172/JCI151601

Lionel Chia,1,2 Bowen Wang,2,3 Jung-Hyun Kim,2 Li Z. Luo,2 Shuai Shuai,2 Iliana Herrera,2 Sophia Y. Chen,4 Liping Li,2 Lingling Xian,2 Tait Huso,2 Mohammad Heydarian,5 Karen Reddy,5 Woo Jung Sung,2 Shun Ishiyama,6,7 Gongbo Guo,2 Elizabeth Jaffee,8 Lei Zheng,8 Leslie M. Cope,8,9 Kathy Gabrielson,7 Laura Wood,1,6,8 and Linda Resar1,2,3,6,8

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Chia, L. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Wang, B. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Kim, J. in: JCI | PubMed | Google Scholar |

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Luo, L. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Shuai, S. in: JCI | PubMed | Google Scholar |

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Herrera, I. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Chen, S. in: JCI | PubMed | Google Scholar |

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Li, L. in: JCI | PubMed | Google Scholar |

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Xian, L. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Huso, T. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Heydarian, M. in: JCI | PubMed | Google Scholar |

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Reddy, K. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Sung, W. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Ishiyama, S. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Guo, G. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Jaffee, E. in: JCI | PubMed | Google Scholar |

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Zheng, L. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Cope, L. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Gabrielson, K. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Wood, L. in: JCI | PubMed | Google Scholar

1Pathobiology Graduate Program, Department of Pathology and

2Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

3Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

4Department of Surgery,

5Department of Biological Chemistry,

6Department of Pathology,

7Department of Molecular and Comparative Pathobiology,

8Department of Oncology, and

9Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Linda Resar, Johns Hopkins University SOM, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland, 21205, USA. Phone: 410.614.0712; Email: lresar@jhmi.edu.

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Find articles by Resar, L. in: JCI | PubMed | Google Scholar |

Authorship note: LC and BW contributed equally to this work. WSJ is a Visiting Scholar in the Resar laboratory from the Department of Pathology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Published March 15, 2023 - More info

Published in Volume 133, Issue 6 on March 15, 2023
J Clin Invest. 2023;133(6):e151601. https://doi.org/10.1172/JCI151601.
© 2023 Chia et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published March 15, 2023 - Version history
Received: May 28, 2021; Accepted: January 25, 2023 View PDF Abstract

High mobility group A1 (HMGA1) chromatin regulators are upregulated in diverse tumors where they portend adverse outcomes, although how they function in cancer remains unclear. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma composed predominantly of cancer-associated fibroblasts and fibrotic tissue. Here, we uncover an epigenetic program whereby HMGA1 upregulates FGF19 during tumor progression and stroma formation. HMGA1 deficiency disrupts oncogenic properties in vitro while impairing tumor inception and progression in KPC mice and subcutaneous or orthotopic models of PDAC. RNA sequencing revealed HMGA1 transcriptional networks governing proliferation and tumor-stroma interactions, including the FGF19 gene. HMGA1 directly induces FGF19 expression and increases its protein secretion by recruiting active histone marks (H3K4me3, H3K27Ac). Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.

Graphical Abstract Introduction

Pancreatic ductal adenocarcinoma (PDAC) has emerged as a major public health problem in industrialized countries, and its incidence is rising (1–3). PDAC is predicted to become the second leading cause of cancer death in the United States by 2030, overtaking breast, prostate, and colorectal cancer (3). Most patients present with locally advanced or widely metastatic disease, rendering these tumors surgically unresectable (1–3). Even patients with localized tumors amenable to surgical resection will succumb to metastatic disease in almost all cases, suggesting that metastases occur prior to clinical presentation (1). Although previous studies identified mutant KRAS and molecular alterations inactivating CDKN2A, TP53, and TGF-β pathway components, these findings have not translated into improved therapies, nor have they led to effective screening strategies (3, 4, 5). Thus, there is a dire need to discover actionable mechanisms and new therapeutic targets for this exceptionally refractory tumor.

In contrast to many solid tumors, PDACs are characterized by a dense desmoplastic stroma composed of cancer-associated fibroblasts (CAFs) and fibrous scar tissue, although the role of the stroma in tumor progression remains controversial (6–11). While immune cells are found within the stroma, PDACs tend to be “cold” tumors, lacking an antitumor immune response (12). In vitro studies show that CAFs secrete factors that provide inflammatory signals and stimulate tumor growth and progression (9–11). Similarly, biomechanical analyses suggest that a “stiff” tumor microenvironment alters tumor cells to enhance motility and facilitate metastases (13–15). Further, PDAC cells grow faster when implanted with CAFs in mouse xenografts (16). The dense fibroblastic stroma also provides a barrier that prevents cytotoxic therapy from reaching tumor cells (9). Conversely, studies in transgenic mouse models of PDAC found that the stroma restrains tumor growth and progression (7, 8). More recent studies employing single-cell sequencing revealed that stromal cells, like cancer cells, are heterogeneous and impart tumor heterogeneity by creating various interfaces for tumor cells within their microenvironment (9, 17–23). These studies reveal a complex and nuanced role for the PDAC stroma, underscoring the need to better understand its role in disease progression.

Epigenetic alterations have emerged as a fundamental hallmark of cancer that drive tumorigenesis by altering cell fate decisions and differentiation (24). For example, genetic lesions involving the switch/sucrose nonfermentable (SWI/SNF) nucleosome remodeling complex occur in up to 15% of PDAC (25). Mutations affecting histone methyltransferase genes (mixed-lineage leukemia 2 and 3) and the gene encoding the histone demethylase lysine demethylase 6A (KDM6A), also arise in PDAC (25). Accordingly, aberrant methylation patterns are characteristic of PDAC (26–28). Genetic alterations that decrease sirtuin 6 (SIRT6) protein levels, a nutrient sensor and histone deacetylase that removes acetyl groups from histone 3 lysine 9 (H3K9) and histone 3 lysine 56 (H3K56), drive pancreatic tumorigenesis in murine models and predict a subclass of human PDAC with decreased survival (29). Although these discoveries shed light on epigenetic abnormalities in PDAC, they have not led to better therapies.

Overexpression of the gene encoding the chromatin regulator HMGA1 occurs in most aggressive tumors, including PDAC, where high levels portend poor differentiation and adverse outcomes (30–50). The HMGA1 gene is normally expressed during embryogenesis (30, 39, 51) and in adult stem cells (46, 49, 52), but silenced postnatally in most differentiated cells. Through alternatively spliced mRNA, HMGA1 encodes HMGA1a and HMGA1b isoforms, which bind to AT-rich sequences, bend chromatin, and recruit transcriptional complexes to modulate gene expression (31–35, 37, 39, 42, 45–47, 49, 53). When overexpressed in lymphoid cells of transgenic mice, Hmga1 induces aggressive leukemia by upregulating transcriptional networks active in proliferating stem cells, poorly differentiated cancer cells, and inflammation (32, 35, 43, 47, 53). While mechanisms driving HMGA1 expression in cancer are incompletely understood, growth factors (54, 55), cancer-associated mutations, including Kras (56) or mutant Apc (57), and oncogenic transcription factors, such as cMYC (58–60), upregulate HMGA1, suggesting that diverse oncogenic pathways converge on HMGA1 to induce its expression. HMGA1 also cooperates with KRAS in immortalized pancreatic ductal epithelial cells to foster clonogenicity (61), whereas silencing HMGA1 in PDAC cell lines disrupts metastatic progression following orthotopic implantation in immunodeficient mice (62). In intestinal stem cells, HMGA1 amplifies Wnt signals from the stroma and epithelial niches by inducing the expression of genes encoding Wnt agonist receptors (Fzd5/7, Lrp5/6, and Lgr5) and Wnt effectors, such as cMyc and Sox9 (46). Together, these findings suggest that HMGA1 fosters tumor progression through both cell-intrinsic and stromal interactions, though little is known about transcriptional networks and tumor-stroma crosstalk governed by HMGA1 in PDAC.

Here, we uncover what we believe is a previously unknown epigenetic program whereby HMGA1 upregulates transcriptional networks involved in proliferation and tumor-stroma interactions during tumor progression and development of a fibroblastic stroma in PDAC. HMGA1 binds directly to the fibroblast growth factor 19 (FGF19) promoter and recruits active histone marks to induce FGF19 expression and secretion from PDAC cells. Silencing either HMGA1 or FGF19 disrupts phenotypes required for tumor progression. Surprisingly, loss of just a single Hmga1 allele within the pancreatic ductal epithelium significantly prolongs survival in Kras+/LSL-G12D; Trp53+LSL-R172H; Pdx1-Cre (KPC) (63) mice compared with those with both Hmga1 alleles intact. In mice with human PDAC xenografts, silencing HMGA1 or FGF19 depletes tumor-initiating cells while disrupting tumor growth and stroma formation. Moreover, treatment with an FGF receptor 4 (FGFR4) inhibitor, BLU9931, to block FGF19 function (64) recapitulates the effects of HMGA1 or FGF19 silencin