1. Academic Validation
  2. CALB2 drives pancreatic cancer metastasis through inflammatory reprogramming of the tumor microenvironment

CALB2 drives pancreatic cancer metastasis through inflammatory reprogramming of the tumor microenvironment

  • J Exp Clin Cancer Res. 2024 Oct 3;43(1):277. doi: 10.1186/s13046-024-03201-w.
Jinxin Tao # 1 Yani Gu # 2 Zeyu Zhang 1 Guihu Weng 1 Yueze Liu 1 Jie Ren 1 Yanan Shi 3 Jiangdong Qiu 1 Yuanyang Wang 1 Dan Su 1 4 Ruobing Wang 1 5 Yifan Fu 1 Tao Liu 1 Liyuan Ye 1 Wenhao Luo 1 Hao Chen 1 Gang Yang 1 Zhe Cao 1 Hua Huang 1 Jianchun Xiao 1 Bo Ren 1 Lei You 1 Taiping Zhang 6 Yupei Zhao 7
Affiliations

Affiliations

  • 1 General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
  • 2 Institute of Clinical Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Translational Medicine Center, Peking Union Medical College Hospital, Beijing, 100730, China.
  • 3 Biomedical Engineering Facility of National Infrastructures for Translational Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
  • 4 Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 5 Department of General Surgery, China‑Japan Friendship Hospital, Beijing, 100029, China.
  • 6 General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China. tpingzhang@yahoo.com.
  • 7 General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China. zhao8028@263.net.
  • # Contributed equally.
Abstract

Background: Early dissemination to distant organs accounts for the dismal prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Chronic, dysregulated, persistent and unresolved inflammation provides a preferred tumor microenvironment (TME) for tumorigenesis, development, and metastasis. A better understanding of the key regulators that maintain inflammatory TME and the development of predictive biomarkers to identify patients who are most likely to benefit from specific inflammatory-targeted therapies is crucial for advancing personalized Cancer treatment.

Methods: This study identified cell-specific expression of CALB2 in human PDAC through single-cell RNA Sequencing analysis and assessed its clinicopathological correlations in tissue microarray using multi-color immunofluorescence. Co-culture systems containing cancer-associated fibroblasts (CAFs) and patient-derived organoids (PDOs) in vitro and in vivo were employed to elucidate the effects of CALB2-activated CAFs on PDAC malignancy. Furthermore, CUT&RUN assays, luciferase reporter assays, RNA Sequencing, and gain- or loss-of-function assays were used to unravel the molecular mechanisms of CALB2-mediated inflammatory reprogramming and metastasis. Additionally, immunocompetent KPC Organoid allograft models were constructed to evaluate CALB2-induced immunosuppression and PDAC metastasis, as well as the efficacy of inflammation-targeted therapy.

Results: CALB2 was highly expressed both in CAFs and Cancer cells and correlated with an unfavorable prognosis and immunosuppressive TME in PDAC patients. CALB2 collaborated with hypoxia to activate an inflammatory fibroblast phenotype, which promoted PDAC cell migration and PDO growth in vitro and in vivo. In turn, CALB2-activated CAFs upregulated CALB2 expression in Cancer cells through IL6-STAT3 signaling-mediated direct transcription. In Cancer cells, CALB2 further activated CA2+-CXCL14 inflammatory axis to facilitate PDAC metastatic outgrowth and immunosuppression. Genetic or pharmaceutical inhibition of CXCL14 significantly suppressed CALB2-mediated metastatic colonization of PDAC cells in vivo and extended mouse survival.

Conclusions: These findings identify CALB2 as a key regulator of inflammatory reprogramming to promote PDAC metastatic progression. Combination therapy with αCXCL14 monoclonal antibody and gemcitabine emerges as a promising strategy to suppress distant metastasis and improve survival outcomes in PDAC with CALB2 overexpression.

Keywords

CALB2; CXCL14; Cancer-associated fibroblasts; Inflammatory reprogramming; Metastasis; Organoids; Pancreatic cancer.

Figures
Products