Interactive Mechanisms Between Cancer Cells and Macrophages Facilitate Pancreatic Cancer Cachexia

Background

Pancreatic cancer is currently the third leading cause of cancer-related death in the United States and is expected to become the second leading cause of cancer death within the next decade. Unfortunately, more than 80% of pancreatic cancer patients are diagnosed at an advanced stage, with very limited treatment options. Most of these patients will develop cancer cachexia. Cancer cachexia is a severe syndrome characterized by uncontrollable weight loss, loss of appetite, and muscle atrophy. Currently, there are no approved treatments for cancer cachexia in the United States. Therefore, identifying potential therapeutic targets and developing effective treatment strategies has become an urgent problem to solve.

Research Team and Source

This article was published in Cancer Cell on May 13, 2024, and was authored by Mingyang Liu, Yu Ren, Zhijun Zhou, and other researchers. The authors are from multiple research institutions, such as the University of Oklahoma Health Sciences Center, Yale School of Medicine, and Johns Hopkins University School of Medicine. Through collaborative research, these researchers deeply explored the interactive mechanisms between pancreatic cancer cells and the immune microenvironment.

Research Process and Experimental Design

Overall Overview

In this study, the authors investigated the key role of macrophages in pancreatic cancer-induced muscle atrophy and the interaction between macrophages and cancer cells. Specifically, they analyzed how macrophages promote cancer cell TWEAK (TNF-like weak inducer of apoptosis) secretion through the CCL5/TRAF6/NF-κB signaling pathway, thereby leading to muscle atrophy.

Specific Process

1. Association Analysis Researchers first analyzed the association between immune cell proportions and cancer cachexia across multiple cancer types in the TCGA database. They found that a high proportion of macrophages is significantly associated with the high incidence of cancer cachexia and weight loss.

2. Macrophage Depletion Experiments Researchers conducted macrophage depletion experiments using two mouse models (CCR2 knockout and Clodronate treatment). The results showed that macrophage depletion significantly reduced tumor-induced muscle atrophy.

3. Macrophage-Driven Muscle Atrophy The study indicated that when co-cultured with pancreatic cancer cells, macrophages significantly increased cancer cell TWEAK secretion. TWEAK, in turn, activated MuRF1-mediated muscle remodeling, promoting muscle atrophy.

4. Mechanism of Upregulated TWEAK by Macrophage-Derived CCL5 Experiments indicated that under non-contact co-culture conditions with pancreatic cancer cells, CCL5 levels were significantly upregulated in macrophages. Macrophage-secreted CCL5 promoted the transcription and secretion of TWEAK by activating the NF-κB (p65) signaling pathway.

5. Mechanism of Pancreatic Cancer Cell Recruitment of Macrophages Further research found that pancreatic cancer cells recruit and reprogram macrophages through the CCL2/CCR2 axis. This mechanism was validated in pancreatic cancer cell lines with different cachexia potentials.

6. Non-Cell Autonomous Activation Mechanism of TWEAK Researchers validated the crucial role of TWEAK in cancer-induced muscle atrophy through overexpression and knockout experiments. Additionally, k63-linked ubiquitination of TRAF6 played a vital role in the non-cell autonomous activation of TWEAK.

Data Analysis

All experimental data were statistically analyzed using Pearson correlation tests, t-tests, and log-rank tests. Protein expression levels were detected using Western blot and immunohistochemistry staining methods.

Main Results

1. Macrophage Depletion Inhibits Muscle Atrophy Macrophage depletion via CCR2 gene knockout and Clodronate treatment significantly reduced weight loss and lowered the expression levels of muscle atrophy markers MuRF1 and Atrogin-1 in mouse models.

2. Macrophages Promote Cancer Cell TWEAK Secretion Macrophages promote TWEAK secretion in pancreatic cancer cells through the CCL5/NF-κB signaling pathway. TWEAK then activates MuRF1, leading to muscle atrophy.

3. CCL2 Drives Macrophage Recruitment Pancreatic cancer cells recruit and reprogram macrophages through the CCL2/CCR2 axis, forming a positive feedback loop that further promotes TWEAK secretion and muscle atrophy.

4. Role of TRAF6 in Non-Cell Autonomous Activation of TWEAK Macrophages activate k63-linked ubiquitination of TRAF6 through the CCL5 signaling pathway, thereby activating the NF-κB signaling pathway and driving TWEAK secretion.

Conclusion and Value

This study reveals the mechanism by which pancreatic cancer cells, through interactions with macrophages, non-cell autonomously activate TWEAK secretion, leading to muscle atrophy. The results indicate that macrophage depletion and TWEAK inhibition are potential therapeutic targets for pancreatic cancer cachexia. This research not only deepens our understanding of the molecular mechanisms of cancer cachexia but also provides new directions for future treatment strategies.

Highlights

1. Novel Signaling Pathway: The study unveils for the first time that CCL5 upregulates TWEAK secretion through the TRAF6/NF-κB pathway, providing a novel molecular mechanism for cancer cachexia.

2. Potential Therapeutic Targets: Macrophage depletion and TWEAK inhibition as potential therapeutic targets for pancreatic cancer cachexia have significant application value.

3. Multi-level Data Validation: The research has been validated not only at the cellular level and in mouse models but also through clinical samples from human pancreatic cancer patients, making the results more reliable and widely applicable.