A glitch in the matrix: organ-specific matrisomes in metastatic niches

doi:10.1016/j.tcb.2021.08.001

Trends in Cell Biology

Volume 32, Issue 2, February 2022, Pages 110-123

https://doi.org/10.1016/j.tcb.2021.08.001 Get rights and content

Highlights

The extracellular matrix (ECM) of different organs are composed of distinct combinations of matrisomal proteins; metastasis-supportive modifications of these ECMs can be similarly specific to each organ niche while sharing commonalities.
Tumor-derived extracellular vesicles (EVs) home to lung fibroblasts, activate them to cancer-associated fibroblasts (CAFs), and induce a metastasis-supportive microenvironment through collagen and fibronectin deposition and ECM modification.
Immune cells play a significant role in profibrotic changes in the liver and lung metastatic niches.
The bone and brain have unique ECM compositions that produce singular types of modifications.
Increased understanding of metastasis-supportive ECM changes has enabled development of more accurate models and revealed important clinical considerations.
Novel therapeutic approaches for targeting of ECM changes in the premetastatic niche may be beneficial in preventing metastatic relapse.

Modification of the extracellular matrix (ECM) is a critical aspect of developing a metastasis-supportive organ niche. Recent work investigating ECM changes that facilitate metastasis has revealed ways in which different metastatic organ niches are similar as well as the distinct characteristics that make them unique. In this review, we present recent findings regarding how ECM modifications support metastasis in four frequent metastatic sites: the lung, liver, bone, and brain. We discuss ways in which these modifications are shared between metastatic organs as well as features specific to each location. We also discuss areas of technical innovation that could be advantageous to future research and areas of inquiry that merit further investigation.

Section snippets

The extracellular matrix plays an integral role in establishing metastatic niches

Metastasis is responsible for ~90% of cancer-related deaths. Extensive research has focused on what causes cancer cells to spread and how these mechanisms can be targeted or prevented. Since the introduction of Paget’s now renowned ‘seed and soil hypothesis’ in 1889 [1], it has been recognized that the environment of the secondary site plays a crucial role in determining the success of metastatic colonization. More recently, the discovery that the primary tumor can influence the formation of a

Normal ECM composition in common metastatic organs

The tasks of the ECM in all organs are largely consistent: provide structural support for tissues through the ECM architecture and act as a modulator of cell function and phenotype. The latter is achieved by (i) regulating biochemical signals through the sequestration and release of signaling molecules and acting as ligands that drive cellular signaling and (ii) regulating mechanical signals by altering the stiffness of the microenvironment. Thus, remodeling of the ECM is a normal physiological

Lung

The lung is a common site of metastasis for various human cancers, including breast, melanoma, colorectal, bladder, and kidney cancer. Many mouse models of metastasis have a propensity for lung tropism, making it a frequent site of study for PMN characterization. Lung-resident fibroblasts have been identified by numerous studies as key players in metastatic niche formation [9., 10., 11., 12., 13., 14., 15., 16., 17.]. Reprogramming resident fibroblasts and other recruited mesenchymal cells to

ECM changes exhibit organ specificity

As illustrated earlier, ECM changes supporting distinct metastatic niches in different organs share numerous characteristics, including the functions of activated cells, upregulated molecules, and resulting effects. Studies that directly compare metastatic niches of the same tumor type in different organs showed that some ECM-related mechanisms of niche formation are robust across metastatic sites [11]. However, these types of studies also uncovered organ-specific mechanistic nuances. For

Matrisome research perspective

Investigating the metastatic ECM is tricky due to its dynamic nature of subtle and cumulative changes involving a complex array of players. One approach to overcome this has been to integrate multiple analyses to maximize the information that can be gleaned from samples, particularly limited patient tissues. In an MS-based proteomic analysis, the matrisomes of normal colon, CRC, and liver metastases from three patients were compared to identify tissue-specific changes that could act as novel

Concluding remarks

Recent work investigating the ECM has revealed its important role in contributing to the formation of metastasis-supportive environments. The variety of lung metastasizing models provided an abundance of data illuminating the complexity of interactions and modifications that contribute to the PMN. From this point, both robust mechanisms shared between common metastatic organs and unique changes identified through comparative analysis revealed new avenues for research and presented opportunities

Acknowledgments

N.E. is supported by grants from the Israel Science Foundation (ISF), the Israel Cancer Research Fund (ICRF), Worldwide Cancer Research, and the Melanoma Research Alliance (MRA). Figures were created with BioRender.com.

Declaration of interests

The authors declare no competing interests.

Glossary

Basement membrane (BM): sheets of specialized ECM deposited between epithelial tissue and the supporting connective tissue. The BM is typically composed of laminins, type IV collagens, and fibronectin. It functions to provide support, aid tissue compartmentalization, and regulate cell behavior.
Bleomycin: a chemotherapeutic that when instilled into the lungs of mice induces a fibrotic response.
Bone marrow-derived cells (BMDCs): a heterogeneous population of pluripotent stem and progenitor cells, such

References (100)

S. Paget
The distribution of secondary growths in cancer of the breast
Lancet
(1889)
N. Erez
Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner
Cancer Cell
(2010)
C. Chandler
The double edge sword of fibrosis in cancer
Transl. Res.
(2019)
M. Selman et al.
The leading role of epithelial cells in the pathogenesis of idiopathic pulmonary fibrosis
Cell. Signal.
(2020)
A. Sekita
Disruption of collagen/apatite alignment impairs bone mechanical function in osteoblastic metastasis induced by prostate cancer
Bone
(2017)
X. Liu
Metastatic breast cancer cells overexpress and secrete miR-218 to regulate type I collagen deposition by osteoblasts
Breast Cancer Res.
(2018)
S. D’Oronzo
The use of bisphosphonates to treat skeletal complications in solid tumours
Bone
(2021)
M. Clemons
A randomised trial of 4- versus 12-weekly administration of bone-targeted agents in patients with bone metastases from breast or castration-resistant prostate cancer
Eur. J. Cancer
(2021)
R. Carvalho
Impact of breast cancer cells´ secretome on the brain metastatic niche remodeling
Semin. Cancer Biol.
(2020)
E.T. Goddard
Quantitative extracellular matrix proteomics to study mammary and liver tissue microenvironments
Int. J. Biochem. Cell Biol.
(2016)

J. Franco-Barraza

Engineering clinically-relevant human fibroblastic cell-derived extracellular matrices

Methods Cell Biol.

(2020)

B.A. Aguado

Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche

Acta Biomater.

(2016)

A. Naba

The extracellular matrix: tools and insights for the “omics” era

Matrix Biol.

(2016)

C. Rachman-Tzemah

Blocking surgically induced lysyl oxidase activity reduces the risk of lung metastases

Cell Rep.

(2017)

S. Wu

Matrix stiffness-upregulated LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation

J. Exp. Clin. Cancer Res.

(2018)

M. Zenitani

Chemotherapy can promote liver metastasis by enhancing metastatic niche formation in mice

J. Surg. Res.

(2018)

R.N. Kaplan

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

Nature

(2005)

T.R. Cox

The matrix in cancer

Nat. Rev. Cancer

(2021)

J. Winkler

Concepts of extracellular matrix remodelling in tumour progression and metastasis

Nat. Commun.

(2020)

N. George et al.

Extracellular matrix and traumatic brain injury

J. Neuro Res.

(2018)

G. Burgstaller

The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease

Eur. Respir. J.

(2017)

A.D. Kolb et al.

The bone extracellular matrix as an ideal milieu for cancer cell metastases

Cancers

(2019)

H. Nyström

Extracellular matrix proteins in metastases to the liver—composition, function and potential applications

Semin. Cancer Biol.

(2020)

A. Hoshino

Tumour exosome integrins determine organotropic metastasis

Nature

(2015)

C. Zhang

Fibrotic microenvironment promotes the metastatic seeding of tumor cells via activating the fibronectin 1/secreted phosphoprotein 1-integrin signaling

Oncotarget

(2016)

Q. Ji

Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation

Nat. Commun.

(2020)

A. Shinde

Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche

Oncogenesis

(2020)

S. Libring

The dynamic relationship of breast cancer cells and fibroblasts in fibronectin accumulation at primary and metastatic tumor sites

Cancers

(2020)

I. Malanchi

Interactions between cancer stem cells and their niche govern metastatic colonization

Nature

(2012)

O. Shani

Fibroblast-derived IL33 facilitates breast cancer metastasis by modifying the immune microenvironment and driving type 2 immunity

Cancer Res.

(2020)

J. Kong

Extracellular vesicles of carcinoma-associated fibroblasts creates a pre-metastatic niche in the lung through activating fibroblasts

Mol. Cancer

(2019)

J. Gui

Activation of p38α stress-activated protein kinase drives the formation of the pre-metastatic niche in the lungs

Nat. Cancer

(2020)

A. Arina

Tumor-associated fibroblasts predominantly come from local and not circulating precursors

Proc. Natl. Acad. Sci. U. S. A.

(2016)

Y. Sharon

Tumor-derived osteopontin reprograms normal mammary fibroblasts to promote inflammation and tumor growth in breast cancer

Cancer Res.

(2015)

Y. Raz

Bone marrow–derived fibroblasts are a functionally distinct stromal cell population in breast cancer

J. Exp. Med.

(2018)

E. Sahai

A framework for advancing our understanding of cancer-associated fibroblasts

Nat. Rev. Cancer

(2020)

T. Gener Lahav

Melanoma-derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment

Int. J. Cancer

(2019)

A. Santi

Cancer associated fibroblasts: the architects of stroma remodeling

Proteomics

(2018)

M. Pein

Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs

Nat. Commun.

(2020)

D. Öhlund

Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

J. Exp. Med.

(2017)

N. Ershaid

NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis

Nat. Commun.

(2019)

M. Bartoschek

Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing

Nat. Commun.

(2018)

F. Pelon

Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms

Nat. Commun.

(2020)

D. Novo

Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels

Nat. Commun.

(2018)

B.H. Jun

Fibronectin-expressing mesenchymal tumor cells promote breast cancer metastasis

Cancers

(2020)

I. Elia

Breast cancer cells rely on environmental pyruvate to shape the metastatic niche

Nature

(2019)

M. Murgai

KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis

Nat. Med.

(2017)

L. Boulter

The fibrotic and immune microenvironments as targetable drivers of metastasis

Br. J. Cancer

(2021)

D.R. Welch et al.

Defining the hallmarks of metastasis

Cancer Res.

(2019)

J. Franco-Barraza

Matrix-regulated integrin α_vβ₅ maintains α₅β₁-dependent desmoplastic traits prognostic of neoplastic recurrence

eLife

(2017)

Cited by (21)

Machine learning-based approach for automated classification of cell and extracellular matrix using nanomechanical properties
2024, Materials Today Bio
Fibrosis characterized by excess accumulation of extracellular matrix (ECM) due to complex cell-ECM interactions plays a pivotal role in pathogenesis. Herein, we employ the pancreatic ductal adenocarcinoma (PDAC) model to investigate dynamic alterations in nanomechanical attributes arising from the cell-ECM interactions to study the fibrosis paradigm. Several segregated studies performed on cellular and ECM components fail to recapitulate their complex collaboration. We utilized collagen and fibronectin, the two most abundant PDAC ECM components, and studied their nanomechanical attributes. We demonstrate alteration in morphology and nanomechanical attributes of collagen with varying thicknesses of collagen gel. Furthermore, by mixing collagen and fibronectin in various stoichiometry, their nanomechanical attributes were observed to vary. To demonstrate the dynamicity and complexity of cell-ECM, we utilized Panc-1 and AsPC-1 cells with or without collagen. We observed that Panc-1 and AsPC-1 cells interact differently with collagen and vice versa, evident from their alteration in nanomechanical properties. Further, using nanomechanics data, we demonstrate that ML-based techniques were able to classify between ECM as well as cell, and cell subtypes in the presence/absence of collagen with higher accuracy. This work demonstrates a promising avenue to explore other ECM components facilitating deeper insights into tumor microenvironment and fibrosis paradigm.
It's all about the base: stromal cells are central orchestrators of metastasis
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The tumor microenvironment (TME) is an integral part of tumors and plays a central role in all stages of carcinogenesis and progression. Each organ has a unique and heterogeneous microenvironment, which affects the ability of disseminated cells to grow in the new and sometimes hostile metastatic niche. Resident stromal cells, such as fibroblasts, osteoblasts, and astrocytes, are essential culprits in the modulation of metastatic progression: they transition from being sentinels of tissue integrity to being dysfunctional perpetrators that support metastatic outgrowth. Therefore, better understanding of the complexity of their reciprocal interactions with cancer cells and with other components of the TME is essential to enable the design of novel therapeutic approaches to prevent metastatic relapse.
Spatial analysis of the metastatic brain tumor immune and extracellular matrix microenvironment
2023, Advances in Cancer Biology - Metastasis
Metastatic cancer is responsible for the overwhelming majority of cancer-related deaths, with metastatic tumors being the most common neoplasms affecting the central nervous system. One of the major factors regulating tumor biology is the tumor microenvironment. However, little is known about the cellular and non-cellular composition of metastatic brain tumors and how tumor cell ontogeny influences the metastatic brain tumor microenvironment. By integrating multiplex immunohistochemistry and histopathological analysis to investigate composition and the spatial relationship between neoplastic cells, infiltrating and brain resident immune cells and the extracellular matrix, we demonstrate that metastatic brain tumors exhibit differences in extracellular matrix deposition, compared with the most common primary brain tumor type, glioblastoma, and that the dominant immune cell types in metastatic brain tumors are immunosuppressive macrophages, which preferentially localize to extracellular matrix-rich stromal regions.
The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth
2023, Cancer Cell
Cancers represent complex ecosystems comprising tumor cells and a multitude of non-cancerous cells, embedded in an altered extracellular matrix. The tumor microenvironment (TME) includes diverse immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and various additional tissue-resident cell types. These host cells were once considered bystanders of tumorigenesis but are now known to play critical roles in the pathogenesis of cancer. The cellular composition and functional state of the TME can differ extensively depending on the organ in which the tumor arises, the intrinsic features of cancer cells, the tumor stage, and patient characteristics. Here, we review the importance of the TME in each stage of cancer progression, from tumor initiation, progression, invasion, and intravasation to metastatic dissemination and outgrowth. Understanding the complex interplay between tumor cell-intrinsic, cell-extrinsic, and systemic mediators of disease progression is critical for the rational development of effective anti-cancer treatments.
Immune determinants of the pre-metastatic niche
2023, Cancer Cell
Primary tumors actively and specifically prime pre-metastatic niches (PMNs), the future sites of organotropic metastasis, preparing these distant microenvironments for disseminated tumor cell arrival. While initial studies of the PMN focused on extracellular matrix alterations and stromal reprogramming, it is increasingly clear that the far-reaching effects of tumors are in great part achieved through systemic and local PMN immunosuppression. Here, we discuss recent advances in our understanding of the tumor immune microenvironment and provide a comprehensive overview of the immune determinants of the PMN’s spatiotemporal evolution. Moreover, we depict the PMN immune landscape, based on functional pre-clinical studies as well as mounting clinical evidence, and the dynamic, reciprocal crosstalk with systemic changes imposed by cancer progression. Finally, we outline emerging therapeutic approaches that alter the dynamics of the interactions driving PMN formation and reverse immunosuppression programs in the PMN ensuring early anti-tumor immune responses.
Brain extracellular matrix attenuates photodynamic cytotoxicity of glioma cells
2022, Photodiagnosis and Photodynamic Therapy
Citation Excerpt :
In terms of physical structure, dense ECM components hinder the tissue penetration of drugs [5]. In terms of biological characteristics, ECM molecules activate a variety of intracellular signal pathways and affect tumor cell behavior [6]. Gliomas are the most common primary brain tumors, which are often fatal and very difficult to treat.
Glioma is the most common tumor in the central nervous system, which is often accompanied by poor prognosis. Brain extracellular matrix (ECM) plays an important role in regulating the growth and migration of glioma. Photodynamic therapy (PDT) has been an effective method for the treatment of solid tumors by oxidative modifications in recent years, and ECM may have an impact on the cytotoxicity of photodynamic therapy. In this work, we prepared decellularized brain ECM by chemical method to investigate the influence of the photodynamic effect of glioma C6 cells. Compared with decellularized liver ECM, brain ECM reduces PDT cytotoxicity. By observing the content of reactive oxygen species produced by near-infrared light active indocyanine green in cells, it was found that ECM did not affect the production of reactive oxygen species. Therefore, it is speculated that brain ECM may enhance the oxidative stress adaptability of glioma cells through potential signal regulation, or protect photodynamic targeting biomolecules (such as proteins and other cellular components) from oxidation in PDT mediated by indocyanine green and 808 nm laser in glioma cells.

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Trends in Cell Biology

ReviewA glitch in the matrix: organ-specific matrisomes in metastatic niches

Highlights

Section snippets

The extracellular matrix plays an integral role in establishing metastatic niches

Normal ECM composition in common metastatic organs

Lung

ECM changes exhibit organ specificity

Matrisome research perspective

Concluding remarks

Acknowledgments

Declaration of interests

Glossary

Lancet

Cancer Cell

Transl. Res.

Cell. Signal.

Bone

Breast Cancer Res.

Bone

Eur. J. Cancer

Semin. Cancer Biol.

Int. J. Biochem. Cell Biol.

Methods Cell Biol.

Acta Biomater.

Matrix Biol.

Cell Rep.

J. Exp. Clin. Cancer Res.

J. Surg. Res.

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

Nature

The matrix in cancer

Nat. Rev. Cancer

Concepts of extracellular matrix remodelling in tumour progression and metastasis

Nat. Commun.

Extracellular matrix and traumatic brain injury

J. Neuro Res.

The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease

Eur. Respir. J.

The bone extracellular matrix as an ideal milieu for cancer cell metastases

Cancers

Extracellular matrix proteins in metastases to the liver—composition, function and potential applications

Semin. Cancer Biol.

Tumour exosome integrins determine organotropic metastasis

Nature

Fibrotic microenvironment promotes the metastatic seeding of tumor cells via activating the fibronectin 1/secreted phosphoprotein 1-integrin signaling

Oncotarget

Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation

Nat. Commun.

Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche

Oncogenesis

The dynamic relationship of breast cancer cells and fibroblasts in fibronectin accumulation at primary and metastatic tumor sites

Cancers

Interactions between cancer stem cells and their niche govern metastatic colonization

Nature

Fibroblast-derived IL33 facilitates breast cancer metastasis by modifying the immune microenvironment and driving type 2 immunity

Cancer Res.

Extracellular vesicles of carcinoma-associated fibroblasts creates a pre-metastatic niche in the lung through activating fibroblasts

Mol. Cancer

Activation of p38α stress-activated protein kinase drives the formation of the pre-metastatic niche in the lungs

Nat. Cancer

Tumor-associated fibroblasts predominantly come from local and not circulating precursors

Proc. Natl. Acad. Sci. U. S. A.

Tumor-derived osteopontin reprograms normal mammary fibroblasts to promote inflammation and tumor growth in breast cancer

Cancer Res.

Bone marrow–derived fibroblasts are a functionally distinct stromal cell population in breast cancer

J. Exp. Med.

A framework for advancing our understanding of cancer-associated fibroblasts

Nat. Rev. Cancer

Melanoma-derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment

Int. J. Cancer

Cancer associated fibroblasts: the architects of stroma remodeling

Proteomics

Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs

Nat. Commun.

Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

J. Exp. Med.

NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis

Nat. Commun.

Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing

Review
A glitch in the matrix: organ-specific matrisomes in metastatic niches

Matrix-regulated integrin α_vβ₅ maintains α₅β₁-dependent desmoplastic traits prognostic of neoplastic recurrence