BAG6 restricts pancreatic cancer progression by suppressing the release of IL33-presenting extracellular vesicles and the activation of mast cells

被引：6

作者：

Alashkar Alhamwe, Bilal ^{[1
,2
]}

Ponath, Viviane ^{[1
,2
]}

Alhamdan, Fahd ^{[3
,4
]}

Doersam, Bastian ^{[1
,2
]}

Landwehr, Clara ^{[1
,2
]}

Linder, Manuel ^{[1
,2
]}

Pauck, Kim ^{[5
,6
]}

Miethe, Sarah ^{[5
,6
]}

Garn, Holger ^{[5
,6
]}

Finkernagel, Florian ^{[1
,7
]}

Brichkina, Anna ^{[8
,9
,10
]}

Lauth, Matthias ^{[8
,9
]}

Tiwari, Dinesh Kumar ^{[8
,9
]}

Buchholz, Malte ^{[8
,9
]}

Bachurski, Daniel ^{[11
]}

Elmshaeuser, Sabrina ^{[12
]}

Nist, Andrea ^{[12
]}

Stiewe, Thorsten ^{[12
,13
]}

Pogge von Strandmann, Lisa ^{[1
,2
]}

Szymanski, Witold ^{[14
,15
]}

Beutgen, Vanessa ^{[14
,15
]}

Graumann, Johannes ^{[14
,15
]}

Teply-Szymanski, Julia ^{[16
]}

Keber, Corinna ^{[16
]}

Denkert, Carsten ^{[16
]}

Jacob, Ralf ^{[17
]}

Preusser, Christian ^{[1
,2
]}

Pogge von Strandmann, Elke ^{[1
,2
]}

机构：

[1] Philipps Univ, Inst Tumor Immunol, D-35037 Marburg, Germany

[2] Philipps Univ, Core Facil Extracellular Vesicles, D-35043 Marburg, Germany

[3] Boston Childrens Hosp, Dept Anesthesiol Crit Care & Pain Med, Cardiac Anesthesia Div, Boston, MA USA

[4] Harvard Med Sch, Dept Immunol & Anaesthesia, Boston, MA USA

[5] Philipps Univ, Translat Inflammat Res Div, D-35043 Marburg, Germany

[6] Philipps Univ, Core Facil Single Cell Multiom, D-35043 Marburg, Germany

[7] Philipps Univ, Core Facil Bioinformat, D-35043 Marburg, Germany

[8] Philipps Univ, Clin Gastroenterol Endocrinol & Metab, D-35043 Marburg, Germany

[9] Philipps Univ, Ctr Tumor & Immune Biol, D-35043 Marburg, Germany

[10] Philipps Univ, Inst Syst Immunol, D-35043 Marburg, Germany

[11] Univ Cologne, Cluster Excellence Cellular Stress Responses Aging, Cologne, Germany

[12] Philipps Univ, Inst Mol Oncol & Genom Core Facil, German Ctr Lung Res DZL, D-35043 Marburg, Germany

[13] Justus Liebig Univ, Inst Lung Hlth, D-35392 Giessen, Germany

[14] Philipps Univ, Inst Translat Prote, Biochem Pharmacol Ctr, D-35043 Marburg, Germany

[15] Philipps Univ, Biochem Pharmacol Ctr, Core Facil Translat Prote, D-35043 Marburg, Germany

[16] Philipps Univ Marburg, Univ Hosp Marburg UKGM, Inst Pathol, Marburg, Germany

[17] Philipps Univ, Dept Cell Biol & Cell Pathol, D-35043 Marburg, Germany

来源：

CELLULAR & MOLECULAR IMMUNOLOGY | 2024年

关键词：

Pancreatic cancer; EVs; BAG6; Mast cells; TUMOR MICROENVIRONMENT; GROWTH; EXPRESSION; BLOCKADE; PROMOTES;

D O I：

10.1038/s41423-024-01195-1

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer (PC) progression. However, driver genes that direct EV function, the EV-recipient cells, and their cellular response to EV uptake remain to be identified. Therefore, we studied the role of Bcl-2-associated-anthanogene 6 (BAG6), a regulator of EV biogenesis for cancer progression. We used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment (TME) changes in mouse models for pancreatic ductal adenocarcinoma (PDAC) in a Bag6 pro- or deficient background. In vivo data were validated using mouse and human organoids and patient samples. Our data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV release. Mechanistically, this was attributed to mast cell (MC) activation via EV-associated IL33. Activated MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell infiltration. Tumor cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and CD73. Patients with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical relevance. The current study revealed a so far unknown tumor-suppressing activity of BAG6 in PDAC. Bag6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor growth. MC depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration.EVs derived from BAG6-deficient pancreatic cancer cells induce MC activation via IL33/Il1rl1. The secretome of activated MCs induces tumor proliferation and changes in the TME, particularly shifting fibroblasts into an inflammatory cancer-associated fibroblast (iCAF) phenotype. Blocking EVs or depleting MCs restricts tumor growth.

引用

页码：918 / 931

页数：14

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