Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma

Atkinson, A.; Renziehausen, Alexander; Wang, Hexiao; Nigro, Cristiana Lo; Lattanzio, Laura; Merlano, Marco; Rao, Bhavya; Weir, L.; Evans, Alan; Matin, Rubeta; Harwood, Catherine A.; Szlosarek, Peter W.; Pickering, J. Geoffrey; Fleming, Colin; Sim, Van Ren; Li, Su; Vasta, James T.; Raines, Ronald T.; Boniol, Mathieu; Thompson, Alastair; Proby, Charlotte M.; Crook, Tim; Syed, Nelofer

doi:10.1016/j.jid.2018.10.038

Cited by 36 publications

(34 citation statements)

References 25 publications

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“…Our findings are supportive of previous work that HIF-1α enhances expression of PLOD2 and promotes metastasis in sarcoma 56 . In addition, the family of collagen prolyl 4-hydroxylases (P4HAs) has been found to be overexpressed in multiple cancers, promoting cancer progression and is associated with poor clinical outcomes 57,58 . The inhibition of collagen prolyl 4-hydroxylases has been suggested as a strategy to reduce invasiveness of breast cancer 57 and B-cell lymphoma 59 however it remains an unexplored strategy in OS.…”

Section: Discussionmentioning

confidence: 99%

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Song

Pearce

Jiang

et al. 2020

Sci Rep

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osteosarcoma (oS) is the most common bone cancer in children and young adults. Solid tumors are characterized by intratumoral hypoxia, and hypoxic cells are associated with the transformation to aggressive phenotype and metastasis. the proteome needed to support an aggressive osteosarcoma cell phenotype remains largely undefined. To link metastatic propensity to a hypoxia-induced proteotype, we compared the protein profiles of two isogenic canine OS cell lines, POS (low metastatic) and HMpoS (highly metastatic), under normoxia and hypoxia. Label-free shotgun proteomics was applied to comprehensively characterize the hypoxia-responsive proteome profiles in the OS cell phenotypes. Hypothesis-driven parallel reaction monitoring was used to validate the differential proteins observed in the shotgun data and to monitor proteins of which we expected to exhibit hypoxia responsiveness, but which were absent in the label-free shotgun data. We established a "distance" score (|z HMPOS − z POS |), and "sensitivity" score (|z Hypoxia − z Normoxia ) to quantitatively evaluate the proteome shifts exhibited by oS cells in response to hypoxia. evaluation of the sensitivity scores for the proteome shifts observed and principal component analysis of the hypoxia-responsive proteins indicated that both cell types acquire a proteome that supports a Warburg phenotype with enhanced cell migration and proliferation characteristics. Cell migration and glucose uptake assays combined with protein function inhibitor studies provided further support that hypoxia-driven adaption of pathways associated with glycolytic metabolism, collagen biosynthesis and remodeling, redox regulation and immunomodulatory proteins typify a proteotype associated with an aggressive cancer cell phenotype. Our findings further suggest that proteins involved in collagen remodeling and immune editing may warrant further evaluation as potential targets for anti-metastatic treatment strategies in osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Song

Pearce

Jiang

et al. 2020

Sci Rep

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“…Interfering collagen biosynthesis enzymes Collagen genes MiR-129-5p, MiR-29b, MiR-384 [275][276][277] Prolyl 4-hydroxylase Budesonide, catechol, N-oxalylglycine, coumalic acid, ethyl dihydroxybenzoic acid [278][279][280] Heat shock protein 90 1G6-D7, dipalmitoyl-radicicol, 17-DMAG, ganetespib [281][282][283][284] Heat shock protein 47 MiR-29, 1,3-dimethylol-5-FU, AK778, pirfenidone, terutroban [285,286] Matrix metalloproteinases Gallium complex GS2, isoflavonoids, bisphosphonates [287,288] Lysyl oxidases Beta-aminopropionitrile [289] Disturbing cancer cell signaling pathways Snail transcription factors Toosendanin, ponicidin, ferulic acid [290] Hypoxia-inducible factor Tamoxifen, 28-O-propynoylbetulin [291,292] STAT3 signaling pathway VS-4718, stattic, ruxolitinib, S3I-201 [293,294] TGF-β signaling pathway LY2157299 monohydrate, trabedersen, fresolimumab, galunisertib [295,296] NF-κB signaling pathway Honokiol, aspirin, ormeloxifene [297][298][299] AKT signaling pathway Quetiapine, pirfenidone [300] Notch signaling pathway Rovalpituzumab tesirine, taladegib, crenigacestat, MiR-148a [301] Hedgehog signaling pathway Itraconazole, sonidegib, vismodegib [302] RAS signaling pathway Perindopril, losartan [100,303] Tyrosine kinase receptor Bevacizumab, imatinib, ponatinib, dasatinib [304,305] Discoidin domain receptor WRG-28, 7rh, AZD0156 [306][307][308] G protein family receptor AT13148, KD025, Azaindole 1, chelerythrine…”

Section: Effects Of Inhibitors Targeted Sites Of Inhibitors Typical Imentioning

confidence: 99%

The role of collagen in cancer: from bench to bedside

et al. 2019

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Collagen is the major component of the tumor microenvironment and participates in cancer fibrosis. Collagen biosynthesis can be regulated by cancer cells through mutated genes, transcription factors, signaling pathways and receptors; furthermore, collagen can influence tumor cell behavior through integrins, discoidin domain receptors, tyrosine kinase receptors, and some signaling pathways. Exosomes and microRNAs are closely associated with collagen in cancer. Hypoxia, which is common in collagen-rich conditions, intensifies cancer progression, and other substances in the extracellular matrix, such as fibronectin, hyaluronic acid, laminin, and matrix metalloproteinases, interact with collagen to influence cancer cell activity. Macrophages, lymphocytes, and fibroblasts play a role with collagen in cancer immunity and progression. Microscopic changes in collagen content within cancer cells and matrix cells and in other molecules ultimately contribute to the mutual feedback loop that influences prognosis, recurrence, and resistance in cancer. Nanoparticles, nanoplatforms, and nanoenzymes exhibit the expected gratifying properties. The pathophysiological functions of collagen in diverse cancers illustrate the dual roles of collagen and provide promising therapeutic options that can be readily translated from bench to bedside. The emerging understanding of the structural properties and functions of collagen in cancer will guide the development of new strategies for anticancer therapy.

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“…Further analysis of these genes/pathways may prove a rich resource to uncover novel metastasis biology. We found that two such genes, KDELR3 and P4HA2 (a collagen prolyl 4-hydroxylase involved in ECM remodeling and associated with worse clinical outcome in melanoma patients 65 ), from our 4-gene functional validation screen are tightly co-expressed in four independent mouse models and in human melanoma patients. This raises the possibility that expression of some genes within our MetDev cohort may be coordinated and/or networked to realize the complex and dynamic phenotypes exhibited by melanocytic cells during development and metastasis.…”

Section: Discussionmentioning

confidence: 88%

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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Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma

Cited by 36 publications

References 25 publications

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

The role of collagen in cancer: from bench to bedside

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

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