Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility

Kaur, Amanpreet; Ecker, Brett L.; Douglass, Stephen M.; Kugel, Curtis H.; Webster, Marie R.; Almeida, Filipe V.; Somasundaram, Rajasekharan; Hayden, James; Ban, Ehsan; Ahmadzadeh, Hossein; Franco‐Barraza, Janusz; Shah, Neelima; Mellis, Ian A.; Keeney, Frederick; Kossenkov, Andrew V.; Tang, Hsin‐Yao; Yin, Xiangfan; Liu, Qin; Xu, Xiaowei; Fane, Mitchell; Brafford, Patricia; Herlyn, Meenhard; Speicher, David W.; Wargo, Jennifer A.; Tetzlaff, Michael T.; Haydu, Lauren E.; Raj, Arjun; Shenoy, Vivek B.; Cukierman, Edna; Weeraratna, Ashani T.

doi:10.1158/2159-8290.cd-18-0193

Cited by 296 publications

(285 citation statements)

References 62 publications

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“…We here identify an enrichment of ECM organization and trafficking genes within our MetDev cohort, consistent with a known role for these in metastasis [62][63][64] . Further analysis of these genes/pathways may prove a rich resource to uncover novel metastasis biology.…”

Section: Discussionsupporting

confidence: 84%

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

Marie

Sassano

Yang

et al. 2019

Preprint

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Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posited that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover novel metastatic melanoma biology. We used a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, identified melanoblast-specific genes whose expression contributed to metastatic competence, and derived a 43-gene signature that predicted patient survival. We identified a melanoblast gene, KDELR3, whose loss impaired experimental metastasis. In contrast, KDELR1 deficiency enhanced metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover novel targetable pathways for melanoma therapy.Melanoma is an aggressive cancer that frequently progresses to metastatic proficiency. Treatment of metastatic melanoma remains a challenge, highlighting an urgent need to uncover new targets that could be used in the clinic to broaden therapeutic options. In the early 19 th century, Virchow first described cancer cells as being "embryonic-like" 1 . Developmental systems have since proven useful to study melanoma, and melanoma cell plasticity appears to be a key feature of melanoma progression. Melanocyte lineage pathways are a recurring theme in melanoma etiology, reinforcing the importance of uncovering new melanocyte developmental pathways and biology 2-13 . Here we use a genetically engineered mouse (GEM), designed to facilitate the isolation and analysis of developing melanocytes (melanoblasts), to attempt to uncover new targets relevant to melanoma metastasis.Melanocytes are neural crest-derived cells whose development necessitates extensive migration/invasion to populate the skin and other sites 14 . This process requires melanoblasts to adopt a migratory phenotype, to interact with and survive in foreign microenvironments and to colonize distant sites − functions that are analogous to metastatic competence 15 . To complete these processes, the cell may encounter numerous cellular stressors, such as shear stress, nutrient deprivation, hypoxia, lipid stress and oxidative stress 16 . The cellular impact of these stressors converges at the Endoplasmic Reticulum (ER), the organelle tied closely to protein synthesis and responsible for correct protein folding, protein quality control and post-translational modifications.Stress stimuli can result in aberrant ER function, a build-up of unfolded/misfolded proteins (ER stress), and an overwhelmed system. The ER can therefore be viewed as an exquisitely sensitive stress sensor. Upon ER stress insult, the ER launches an immediate counter measure known as of the Unfolded Protein Response (UPR) 17 . T...

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Section: Discussionsupporting

confidence: 84%

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

Marie

Sassano

Yang

et al. 2019

Preprint

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“…In human lung and ovarian tumors we found that T cells preferentially accumulate and migrate in stromal regions that exhibited a loose matrix architecture but not in dense regions (11,38). Likewise, in aged skin, dermal fibroblasts harbor a phenotype similar to CAFs and produce ECM matrices that limit T cell displacements (43). However, in triple-negative breast cancers and in pancreatic tumors T cells were still found in dense networks of collagen fibers (35,44).…”

Section: Discussionmentioning

confidence: 86%

Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

Nicolas‐Boluda

Vaquero

Barrin

et al. 2020

Preprint

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Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing 5 preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase (LOX) was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.

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“…However, in cancer, disruption of BMs is commonly observed. A series of recent studies (40,41) demonstrated that the ECM molecule hyaluronan and proteoglycan link protein-1 (HAPLN1) decreased with aging of the ECM. This resulted in disruption of the vascular BM and increased vessel permeability, leading to subsequently enhanced FIGURE 1 | Role of the extracellular matrix in driving progression through stages of the metastatic cascade.…”

Section: Invasion and Intravasationmentioning

confidence: 99%

Cancer Metastasis: The Role of the Extracellular Matrix and the Heparan Sulfate Proteoglycan Perlecan

et al. 2020

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Cancer metastasis is the dissemination of tumor cells to new sites, resulting in the formation of secondary tumors. This process is complex and is spatially and temporally regulated by intrinsic and extrinsic factors. One important extrinsic factor is the extracellular matrix, the non-cellular component of tissues. Heparan sulfate proteoglycans (HSPGs) are constituents of the extracellular matrix, and through their heparan sulfate chains and protein core, modulate multiple events that occur during the metastatic cascade. This review will provide an overview of the role of the extracellular matrix in the events that occur during cancer metastasis, primarily focusing on perlecan. Perlecan, a basement membrane HSPG is a key component of the vascular extracellular matrix and is commonly associated with events that occur during the metastatic cascade. Its contradictory role in these events will be discussed and we will highlight the recent advances in cancer therapies that target HSPGs and their modifying enzymes.

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Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility

Cited by 296 publications

References 62 publications

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

Cancer Metastasis: The Role of the Extracellular Matrix and the Heparan Sulfate Proteoglycan Perlecan

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