Dataset Information

Ym1⁺ macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer.

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 in vitro, 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.

SUBMITTER: Fleming Martinez AK

PROVIDER: S-EPMC9118688 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Ym1<sup>+</sup> macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer.

Fleming Martinez Alicia K AK Döppler Heike R HR Bastea Ligia I LI Edenfield Brandy H BH Liou Geou-Yarh GY Storz Peter P

iScience 20220429 5

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 <i>in vitro</i>, 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 activ ...[more]

PMID: 35602933

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Project description:Pancreatic ductal adenocarcinoma is a devastating disease with a dismal prognosis. Therapeutic interventions are largely ineffective. A better understanding of the pathophysiology is required. Ion channels contribute substantially to the "hallmarks of cancer." Their expression is dysregulated in cancer, and they are "misused" to drive cancer progression, but the underlying mechanisms are unclear. Ion channels are located in the cell membrane at the interface between the intracellular and extracellular space. They sense and modify the tumor microenvironment which in itself is a driver of PDAC aggressiveness. Ion channels detect, for example, locally altered proton and electrolyte concentrations or mechanical stimuli and transduce signals triggered by these microenvironmental cues through association with intracellular signaling cascades. While these concepts have been firmly established for other cancers, evidence has emerged only recently that ion channels are drivers of PDAC aggressiveness. Particularly, they appear to contribute to two of the characteristic PDAC features: the massive fibrosis of the tumor stroma (desmoplasia) and the efficient immune evasion. Our critical review of the literature clearly shows that there is still a remarkable lack of knowledge with respect to the contribution of ion channels to these two typical PDAC properties. Yet, we can draw parallels from ion channel research in other fibrotic and inflammatory diseases. Evidence is accumulating that pancreatic stellate cells express the same "profibrotic" ion channels. Similarly, it is at least in part known which major ion channels are expressed in those innate and adaptive immune cells that populate the PDAC microenvironment. We explore potential therapeutic avenues derived thereof. Since drugs targeting PDAC-relevant ion channels are already in clinical use, we propose to repurpose those in PDAC. The quest for ion channel targets is both motivated and complicated by the fact that some of the relevant channels, for example, KCa3.1, are functionally expressed in the cancer, stroma, and immune cells. Only in vivo studies will reveal which arm of the balance we should put our weights on when developing channel-targeting PDAC therapies. The time is up to explore the efficacy of ion channel targeting in (transgenic) murine PDAC models before launching clinical trials with repurposed drugs.

Dataset Information

Ym1⁺ macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer.

Publications

Ym1<sup>+</sup> macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer.

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Dataset Information

Ym1+ macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer.

Publications

Ym1<sup>+</sup> macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Ym1⁺ macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer.