The Sun Yu research group of the Institute of Nutrition and Health reported the mechanism of action of a new microenvironment factor on the malignant evolution of tumors

Cellular senescence is a unique cellular state with a variety of well-defined and stable cellular characteristics
.
Among them, the Senescence-associated secretory phenotype (SASP) allows it to perform complex signaling functions
to other cells in the microenvironment.
In the elderly population, including chronic inflammatory formation processes and local spaces of tumor microenvironment, the secretory phenotype of SASP has a pathological effect
on the progression of various diseases.
Therefore, the study of SASP-related factors and their molecular mechanisms and intervention pathways in the tissue microenvironment of tumors and other diseases has far-reaching guiding significance
for the clinical treatment of geriatric diseases.

This study confirmed that epiregulin (EREG) expression is significantly upregulated under aging-induced conditions of DNA damage type by performing in vitro drug simulation treatment on human primary stromal cells based on the stress of current clinical chemotherapy, and an association between this factor and senescent cells in the microenvironment has not been reported
。 At the same time, the analysis of cancer samples before and after chemotherapy in patients with clinical prostate cancer and breast cancer also found that EREG expression was significantly upregulated in senescent paracarcinomic stromal cells
.
Mechanically, DNA damage leads to nuclear translocation of transcription factors such as NF-κB in stromal cells and binding to multiple sites in the ELEG promoter region, thereby promoting the upregulation of EREG expression after cell senescence
。 At the same time, the researchers also noted that other aging-related factors include transcription factor C/EBP activation, changes in the openness of DNA space, and changes in epigenetic modifications that promote EREG transcription
.

In the tumor microenvironment, EREGs released by senescent cells activate EGFR receptors including MAPK, AKT/MTOR, and JAK/ STAT and other downstream signaling pathways, thereby inducing malignant phenotypes such as cancer cell proliferation, migration, and invasion, and eventually causing significant drug resistance of
cancer cells.
Through RNA-Seq analysis, the researchers found that a ubiquitin ligase MARCHF4 was significantly upregulated
in matrix EREG-activated cancer cells.
MARCHF4 can downregulate the expression of E-cadherin in cancer cells and inhibit apoptosis of cancer cells, thereby leading to the occurrence of
tumor drug resistance.
In mouse models, the combination of EREG monoclonal antibody and EGFR monoclonal antibody significantly reduced tumor volume and significantly prolonged disease-free progression survival in
mice.
It is worth mentioning that there is a significant negative correlation between the expression level of EREG in the microenvironment in vivo cancer patients and their long-term survival in the post-clinical treatment stage, and can be used as a novel marker
for the prognosis of patients (including multiple cancer types).

In summary, this work deeply discovers and accurately explains the pathological function and regulatory mechanism of the aging-related secretion factor EREG in the tumor microenvironment, and reveals its great potential and important value
in future translational medicine and clinical applications.
Changxu Wang, a doctoral student at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, and Long Qilai, Department of Urology, Zhongshan Hospital of Fudan University, are the co-first authors
of the paper.
Yu Sun, a researcher at the Shanghai Institute of Nutrition and Health, is the corresponding author
of the paper.
The work was supported
by the Ministry of Science and Technology, the National Natural Science Foundation of China, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Commission, as well as the public technology platform of the institute-level center of the Institute of Nutrition and Health.

Links to papers: https://doi.
org/10.
1038/s41388-022-02476-7