Clinical functional proteomics of intercellular signalling in pancreatic cancer

Peiwu Huang ¹, Weina Gao ¹, Changying Fu ¹

¹State Key Laboratory of Medical Proteomics and Shenzhen Key Laboratory of Functional Proteomics, Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, School of Science and Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China.
²Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³Key Laboratory of Multi-Cell Systems, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
⁴Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA. shiyu.xy@gmail.com.
⁵Bristol Myers Squibb, San Diego, CA, USA. shiyu.xy@gmail.com.
⁶Key Laboratory of Multi-Cell Systems, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China. dong.gao@sibcb.ac.cn.
⁷Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China. dong.gao@sibcb.ac.cn.
⁸Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. ryqin@tjh.tjmu.edu.cn.
⁹Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
¹⁰State Key Laboratory of Medical Proteomics and Shenzhen Key Laboratory of Functional Proteomics, Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, School of Science and Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China. tianrj@sustech.edu.cn.

⁰State Key Laboratory of Medical Proteomics and Shenzhen Key Laboratory of Functional Proteomics, Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, School of Science and Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China.

Nature +

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November 13, 2024

View abstract on PubMed

Summary

Researchers developed TMEPro, a proteomic strategy to uncover intercellular communication in pancreatic cancer. This revealed a stromal PDGFR-PTPN11-FOS signaling axis and AXL shedding, offering new therapeutic targets for pancreatic ductal adenocarcinoma.

Area Of Science

Oncology
Proteomics
Cancer Biology

Background

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a complex tumor microenvironment (TME).
Intercellular signaling between cancer and stromal cells significantly impacts PDAC progression and patient prognosis.
Understanding these interactions is crucial for developing effective therapeutic strategies.

Purpose Of The Study

To develop and apply a multidimensional proteomic strategy (TMEPro) for deep profiling of the PDAC TME.
To identify intercellular signaling pathways, particularly those involving tyrosine phosphorylation, between cancer and stromal cells.
To investigate the role of plasma membrane protein shedding in PDAC TME regulation and identify potential therapeutic targets.

Main Methods

Development of TMEPro, a proteomic strategy for analyzing glycosylated secreted and plasma membrane proteins.
Application of TMEPro to 100 human pancreatic tissue samples for deep proteomic profiling.
Investigation of temporal dynamics in a genetically engineered mouse model of PDAC.
Functional analysis of identified signaling axes and protein shedding mechanisms.

Main Results

TMEPro enabled deep profiling of the PDAC proteome, defining cell origins and paracrine crosstalk.
Reciprocal signaling between stromal and cancer cells was identified via the PDGFR-PTPN11-FOS axis.
Matrix-metalloprotease-mediated shedding of AXL receptor tyrosine kinase ectodomain was revealed as a key regulatory mechanism.
Shed AXL levels correlated with lymph node metastasis; AXL inhibition showed synergistic effects on cancer cell growth.

Conclusions

TMEPro is a versatile clinical proteomic strategy for dissecting the PDAC TME.
The study identified novel intercellular signaling pathways and the significance of AXL shedding in PDAC.
These findings provide a resource for discovering new diagnostic and therapeutic targets for pancreatic cancer.

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