Ym1 Macrophages Orchestrate Fibrosis, Lesion Growth, and Progression During Development of Murine Pancreatic Cancer

Overview

Journal iScience

Publisher Cell Press

Date 2022 May 23

PMID 35602933

Authors

Alicia K Fleming Martinez

Heike R Doppler

Ligia I Bastea

Brandy H Edenfield

Geou-Yarh Liou

Peter Storz

Affiliations

Soon will be listed here.

Abstract

Desmoplasia around pancreatic lesions is a barrier for immune cells and a hallmark of developing and established pancreatic cancer. However, the contribution of the innate immune system to this process is ill-defined. Using the KC mouse model and primary cells , we show that alternatively activated macrophages (AAM) crosstalk with pancreatic lesion cells and pancreatic stellate cells (PSCs) to mediate fibrosis and progression of lesions. TGFβ1 secreted by AAM not only drives activation of quiescent PSCs but also in activated PSCs upregulates expression of TIMP1, a factor previously shown as crucial in fibrosis. Once activated, PSCs auto-stimulate proliferation via CXCL12. Furthermore, we found that TIMP1/CD63 signaling mediates PanIN lesion growth and TGFβ1 contributes to a cadherin switch and drives structural collapse of lesions, indicating a potential progression step. Taken together, our data indicate TGFβ1 produced by Ym1+ AAM as a major driver of processes that initiate the development of pancreatic cancer.

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