Hyaluronic acid fuels pancreatic cancer cell growth
- University of Michigan, United States
- The University of Texas MD Anderson Cancer Center, United States
- Memorial Sloan Kettering Cancer Center, United States
- University of Southern California, United States
Abstract
Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in human PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not preclude the growth of human tumor xenografts in mice, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. We found that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; raw images have been provided for all western blots in the Source Data file.
Article and author information
Author details
Funding
National Cancer Institute (Cancer Biology Training Grant,T32AI007413)
- Peter K Kim
- Samuel A Kerk
Thompson Family Foundation (Research Grant)
- Kayvan R Keshari
STARR Cancer Consortium (Research Grant)
- Kayvan R Keshari
National Cancer Institute (Cancer Center Support Grant,P30CA008748)
- Kayvan R Keshari
American Association for Cancer Research (Pathway to Leadership award,13-70-25-LYSS)
- Costas Lyssiotis
V Foundation for Cancer Research (Junior Scholar Award,V2016-009)
- Costas Lyssiotis
Sidney Kimmel Foundation (Kimmel Scholar Award,SKF-16-005)
- Costas Lyssiotis
American Association for Cancer Research (NextGen Grant for Transformative Cancer Research,17-20-01-LYSS)
- Costas Lyssiotis
National Cancer Institute (Cancer Center Support Grant,P30 CA046592)
- Costas Lyssiotis
National Cancer Institute (R37CA237421)
- Costas Lyssiotis
National Cancer Institute (R01CA248160)
- Costas Lyssiotis
National Cancer Institute (Predoctoral Fellowship,F31CA243344)
- Peter K Kim
National Cancer Institute (R01CA244931)
- Costas Lyssiotis
National Institutes of Health (U24DK097153)
- Costas Lyssiotis
Charles Woodson Research Fund (Research Support)
- Costas Lyssiotis
UM Pediatric Brain Tumor Initiative (Research Support)
- Costas Lyssiotis
National Cancer Institute (F99/K00CA264414)
- Samuel A Kerk
National Institute of Child Health and Human Development (T32HD007505)
- Megan Radyk
National Cancer Institute (Pathway to Independence Award,K99CA241357)
- Christopher J Halbrook
National Institute of Diabetes and Digestive and Kidney Diseases (Postdoctoral Support,P30DK034933)
- Christopher J Halbrook
National Cancer Institute (F31CA24745701)
- Samuel A Kerk
National Cancer Institute (R01CA237466)
- Kayvan R Keshari
National Cancer Institute (R01CA252037)
- Kayvan R Keshari
National Cancer Institute (R21CA212958)
- Kayvan R Keshari
Stand Up To Cancer (Research Grant)
- Kayvan R Keshari
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experiments were conducted in accordance with the Office of Laboratory Animal Welfare and approved by the Institutional Animal Care and Use Committees of the University of Michigan. Protocol#: PRO00008877
Copyright
© 2021, Kim et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 9,663
- views
-
- 955
- downloads
-
- 67
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Hyaluronic acid fuels pancreatic cancer cell growth
eLife 10:e62645.
https://doi.org/10.7554/eLife.62645
Further reading
-
- Cancer Biology
- Immunology and Inflammation
The current understanding of humoral immune response in cancer patients suggests that tumors may be infiltrated with diffuse B cells of extra-tumoral origin or may develop organized lymphoid structures, where somatic hypermutation and antigen-driven selection occur locally. These processes are believed to be significantly influenced by the tumor microenvironment through secretory factors and biased cell-cell interactions. To explore the manifestation of this influence, we used deep unbiased immunoglobulin profiling and systematically characterized the relationships between B cells in circulation, draining lymph nodes (draining LNs), and tumors in 14 patients with three human cancers. We demonstrated that draining LNs are differentially involved in the interaction with the tumor site, and that significant heterogeneity exists even between different parts of a single lymph node (LN). Next, we confirmed and elaborated upon previous observations regarding intratumoral immunoglobulin heterogeneity. We identified B cell receptor (BCR) clonotypes that were expanded in tumors relative to draining LNs and blood and observed that these tumor-expanded clonotypes were less hypermutated than non-expanded (ubiquitous) clonotypes. Furthermore, we observed a shift in the properties of complementarity-determining region 3 of the BCR heavy chain (CDR-H3) towards less mature and less specific BCR repertoire in tumor-infiltrating B-cells compared to circulating B-cells, which may indicate less stringent control for antibody-producing B cell development in tumor microenvironment (TME). In addition, we found repertoire-level evidence that B-cells may be selected according to their CDR-H3 physicochemical properties before they activate somatic hypermutation (SHM). Altogether, our work outlines a broad picture of the differences in the tumor BCR repertoire relative to non-tumor tissues and points to the unexpected features of the SHM process.
-
- Cancer Biology
- Computational and Systems Biology
Effects from aging in single cells are heterogenous, whereas at the organ- and tissue-levels aging phenotypes tend to appear as stereotypical changes. The mammary epithelium is a bilayer of two major phenotypically and functionally distinct cell lineages: luminal epithelial and myoepithelial cells. Mammary luminal epithelia exhibit substantial stereotypical changes with age that merit attention because these cells are the putative cells-of-origin for breast cancers. We hypothesize that effects from aging that impinge upon maintenance of lineage fidelity increase susceptibility to cancer initiation. We generated and analyzed transcriptomes from primary luminal epithelial and myoepithelial cells from younger <30 (y)ears old and older >55 y women. In addition to age-dependent directional changes in gene expression, we observed increased transcriptional variance with age that contributed to genome-wide loss of lineage fidelity. Age-dependent variant responses were common to both lineages, whereas directional changes were almost exclusively detected in luminal epithelia and involved altered regulation of chromatin and genome organizers such as SATB1. Epithelial expression variance of gap junction protein GJB6 increased with age, and modulation of GJB6 expression in heterochronous co-cultures revealed that it provided a communication conduit from myoepithelial cells that drove directional change in luminal cells. Age-dependent luminal transcriptomes comprised a prominent signal that could be detected in bulk tissue during aging and transition into cancers. A machine learning classifier based on luminal-specific aging distinguished normal from cancer tissue and was highly predictive of breast cancer subtype. We speculate that luminal epithelia are the ultimate site of integration of the variant responses to aging in their surrounding tissue, and that their emergent phenotype both endows cells with the ability to become cancer-cells-of-origin and represents a biosensor that presages cancer susceptibility.
