Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression

Zhu, Yuechun; Herndon, John M.; Sojka, Dorothy K.; Kim, Ki Wook; Knolhoff, Brett L.; Zuo, Chong; Cullinan, Darren R.; Luo, Jingqin; Bearden, Audrey R.; Lavine, Kory J.; Yokoyama, Wayne M.; Hawkins, William G.; Fields, Ryan C.; Randolph, Gwendalyn J.; DeNardo, David G.

doi:10.1016/j.immuni.2017.08.018

Cited by 185 publications

(179 citation statements)

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“…In pancreatic ductal adenocarcinoma (PDAC) for example, a proportion of TAMs, shown to be of embryonic origin, assumes functions independent of bone marrow-derived monocytes. 39 In transgenic K-ras LSL-G12D/+/ p53 R127H/+ /PdxCre harboring PDAC tumors, these tissue-resident macrophages are capable of proliferation and self-expansion, and they express high levels of pro-fibrotic ECM-remodeling factors that facilitate tumor progression. 39 Importantly, the suppression of the CSF1/CSF1R axis in this tumor model does not significantly affect this TAM subpopulation (although it partially reduces tumor size), suggesting that PDAC progression is in part regulated by tissue-resident TAMs.…”

Section: Recruitment and Maturation Of Tams In The Tumor Microenvironmentioning

confidence: 99%

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

Sanchez

Borriello

Entenberg

et al. 2019

Journal of Leukocyte Biology

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Macrophages represent a heterogeneous group of cells, capable of carrying out distinct functions in a variety of organs and tissues. Even within individual tissues, their functions can vary with location. Tumor‐associated macrophages (TAMs) specialize into three major subtypes that carry out multiple tasks simultaneously. This is especially true in the context of metastasis, where TAMs establish most of the cellular and molecular prerequisites for successful cancer cell dissemination and seeding to the secondary site. Perivascular TAMs operate in the perivascular niche, where they promote tumor angiogenesis and aid in the assembly of intravasation sites called tumor microenvironment of metastasis (TMEM). Streaming TAMs co‐migrate with tumor cells (irrespective of the perivascular niche) and promote matrix remodeling, tumor cell invasiveness, and an immunosuppressive local microenvironment. Premetastatic TAMs are recruited to the premetastatic niche, where they can assist in tumor cell extravasation, seeding, and metastatic colonization. The dynamic interplay between TAMs and tumor cells can also modify the ability of the latter to resist cytotoxic chemotherapy (a phenotype known as environment‐mediated drug resistance) and induce chemotherapy‐mediated pro‐metastatic microenvironmental changes. These observations suggest that future therapeutics should be designed to target TAMs with the aim of suppressing the metastatic potential of tumors and rendering chemotherapy more efficient.

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Section: Recruitment and Maturation Of Tams In The Tumor Microenvironmentioning

confidence: 99%

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

Sanchez

Borriello

Entenberg

et al. 2019

Journal of Leukocyte Biology

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“…Zhu et al have recently demonstrated that embryonicderived tissue resident macrophages play key roles in the pathogenesis of a mouse model of pancreatic cancer, distinct from effects of CCR2-dependent monocyte-derived macrophages [102].…”

Section: Note Added In Proofmentioning

confidence: 99%

Nonresolving macrophage‐mediated inflammation in malignancy

Murray

2017

The FEBS Journal

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Tumors are populated with different cells of the immune system, each of which has the potential for pro-or antitumor functions. Macrophages are the numerically dominant type of myeloid cell in cancer and are suspected of having predominantly protumor functions. Key questions in cancer research concern the relationships between macrophages and anatomically different kinds of cancers, what specific properties of macrophages are involved in protumor functions and whether either macrophage numbers or functions can be modulated to enhance existing cancer therapies, for example, by reducing the immunosuppressive milieu such that anti-tumor T cells can provoke antitumor immunity. Accordingly, several antimacrophage preclinical modalities have been attempted and revealed substantial clinical barriers to their use. Therefore, understanding and targeting the specific pathways associated with protumor functions of macrophages, rather than macrophages themselves is a promising approach for both basic research and therapeutic development.

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“…Collagen VI synthesis has also been demonstrated in monocytes associated with triple-negative breast cancer xenografts [132]. More recently, it has been demonstrated that pancreatic ductal adenocarcinoma embryonically derived TAMs, but not Ly6C hi monocyte-derived TAMs, exhibit a profibrotic function manifested by their expression of genes encoding for various types of collagen and their direct ex vivo production of collagen type I [133]. The ability of macrophages to acquire a fibroblast-like phenotype expressed by their direct synthesis of specific collagen subtypes is further supported by studies in renal fibrosis [134] and atherosclerotic plaques [135].…”

Section: Tams As Builders Of the Tumorigenic Ecm Nichementioning

confidence: 99%

“…Notably, TAMs also produce proteins associated with collagen assembly and organization (Scheme 1). A specific example is their expression of SPARC glycoprotein; a collagen chaperone and a master stromal regulator [17,92,133]. Immune cell-derived SPARC has shown to be important for the assembly and organization of collagenous matrix [138,139].…”

Section: Tams As Builders Of the Tumorigenic Ecm Nichementioning

confidence: 99%

“…TGM2 expression in various cancer cell types has been linked to increased drug resistance, cell survival, invasiveness, metastasis and poor patient survival [140]. Moreover, pancreatic tumor embryonic-derived TAMs express genes encoding for the collagen cross-linkers lysyl oxidase (LOX) and LOX-like protein 1 (LOXL1) [133].…”

Section: Tams As Builders Of the Tumorigenic Ecm Nichementioning

confidence: 99%

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Phagocyte—extracellular matrix crosstalk empowers tumor development and dissemination

Varol

Sagi

2017

The FEBS Journal

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Phagocytes, such as tumor-associated macrophages (TAMs) and tumorassociated neutrophils (TANs), are abundant in the stroma of experimental and human tumors and are locally educated to mediate important biological functions that profoundly affect tumor initiation, growth, and dissemination. Of considerable importance is the noncellular component of the tumor microenvironment, namely-the extracellular matrix (ECM). This milieu is often overlooked due to its complexity and vast heterogeneity. Biophysical and biomechanical cues provided by the dynamically evolving tumorigenic ECM fundamentally modulate every behavioral facet of the cancer cells and of associated stromal cells. In this review, we discuss the intricate interplay between phagocytes and ECM that are lined up to support tumor progression. TAMs and TANs shape the tumorigenic ECM by providing key matrix-remodeling enzymes and structural proteins and in turn, the altered tumor ECM modulates their migration and function. A better mechanistic comprehension of this reciprocal dependence has exciting implications for the development of new therapeutic options for cancer.Abbreviations 3D, Three-dimensional; ADAM, a disintegrin and metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin

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Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression

Cited by 185 publications

References 0 publications

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

Nonresolving macrophage‐mediated inflammation in malignancy

Phagocyte—extracellular matrix crosstalk empowers tumor development and dissemination

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