Cancer-associated fibroblast heterogeneity is associated with organ-specific metastasis in pancreatic ductal adenocarcinoma.

abstract cc by

AbstractBackgroundMetastasis occurs in the majority of pancreatic ductal adenocarcinoma (PDAC) patients at diagnosis or following resection. Patients with liver metastasis and those with lung metastasis have significantly different prognosis. Here, we sought to understand how cancer-associated fibroblasts (CAFs) play roles in the development of organ-specific metastasis.MethodsPDAC tumor cell lines established from the primary tumors with liver and lung metastasis potentials, respectively, in Kras/p53 mutation conditional knock-in (KPC) mice were co-cultured with matched CAFs or mouse mesenchymal stem cells. CAFs were isolated from metastases and subjected to DNA methylation and whole transcriptomic RNA sequencing analysis.ResultsThe ability of mouse PDAC tumor cell lines in developing liver or lung-specific metastases was demonstrated in orthotopic models. Tumor cells associated with liver metastasis potential, but not those associated with lung metastasis potential, induced the methylation of metabolism genes including NQO1 and ALDH1a3 and subsequent downregulated mRNA expression of a broader group of metabolism genes in CAFs. DNA methylation and downregulation of metabolism genes in CAFs in liver metastasis, but not those in lung metastasis, appeared to be regulated by DNA methyltransferase. Tumor cells associated with liver metastasis potential, but not those associated with lung metastasis potential, induce inflammatory CAF (iCAF) signatures. CAFs from liver metastasis demonstrated a more homogenous iCAF phenotype, whereas CAFs from lung metastasis maintained the heterogeneity.ConclusionsPDAC with organ-specific metastatic potentials has different capacities in inducing methylation of metabolism genes in CAFs, modulating CAF phenotypes, and resulting in different levels of heterogeneity of CAFs in different metastatic niches.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13045-021-01203-1.Keywords: DNA methylation, Cancer-associated fibroblast, Heterogeneity, Organ-specific metastasis, Pancreatic cancer

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authors' contributions cc by

LZ and JZ conceived the concept; XP, JZ, and LZ designed the research studies. XP, JZ, QX, MZ, and KF conducted experiments, acquired and analyzed the data. XP, JZ, and LZ wrote the manuscript. All authors read and approved the final manuscript.

funding cc by

This work was supported by an NIH grant R01 CA169702 (LZ), an NIH Grant R01 CA197296 (LZ), a National Cancer Institute Specialized Programs of Research Excellence in Gastrointestinal Cancers Grant P50 CA062924 (LZ), and a Sidney Kimmel Comprehensive Cancer Center Grant P30 CA006973.

availability of data and materials cc by

RNA sequencing data are provided as supplement materials.

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Not applicable.

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competing interests cc by

LZ receives grant support from Bristol-Meyer Squibb, Merck, iTeos, Amgen, NovaRock, Inxmed, and Halozyme, and received the royalty for licensing GVAX to Aduro Biotech. LZ is a paid consultant/Advisory Board Member at Biosion, Alphamab, NovaRock, Akrevia/Xilio, Ambrx, Novagenesis, Datarevive, Snow Lake Capitals, and Mingruzhiyao. LZ holds shares at Alphamab and Mingruzhiyao.

contributor information cc by

Jiaojiao Zhou, Email: zhoujj@zju.edu.cn. Lei Zheng, Email: lzheng6@jhmi.edu.

data availability statement cc by

RNA sequencing data are provided as supplement materials.