scholarly journals Increased PHGDH expression uncouples hair follicle cycle progression and promotes inappropriate melanin accumulation

2018 ◽  
Author(s):  
Katherine R. Mattaini ◽  
Mark R. Sullivan ◽  
Allison N. Lau ◽  
Brian P. Fiske ◽  
Roderick T. Bronson ◽  
...  
Keyword(s):  
Hair Follicle ◽  
Copy Number ◽  
Copy Number Gain ◽  
Hair Follicles ◽  
Gene Copy ◽  
Human Cancers ◽  
Normal Melanocyte ◽  
Hair Follicle Cycle ◽  
Serine Biosynthesis ◽  
Insight Into

SUMMARYCopy number gain of the PHGDH gene that encodes the first enzyme of the serine biosynthesis pathway is found in some human cancers, including a subset of melanomas. In order to study the effect of increased PHGDH expression in tissues in vivo, we generated mice harboring a PHGDHtetO allele that allows tissue-specific, doxycycline-inducible PHGDH expression. Tissues and cells derived from PHGDHtetO mice exhibit increased serine biosynthesis. Histological examination of skin tissue from PHGDHtetO mice reveals the presence of melanin granules in anagen II hair follicles, despite the fact that melanin synthesis is normally closely coupled to the hair follicle cycle and does not begin until later in the cycle. This phenotype occurs in the absence of any global change in hair follicle cycle timing. The inappropriate presence of melanin early in the hair follicle cycle following PHGDH expression is also accompanied by increased melanocyte abundance in anagen II skin. Together, these data support a model in which PHGDH expression affects melanocyte proliferation and/or differentiation and may provide insight into how PHGDH expression impacts normal melanocyte biology to promote melanoma.SIGNIFICANCEThe significance behind copy number gain of PHGDH in human cancers is unclear. In this study, we generate a mouse model that mimics PHGDH gene copy number gain and characterize its effect on normal tissues. Increased PHGDH expression yields a phenotype of aberrant melanin production, which indicates that PHGDH expression may play a role in normal melanocyte biology. This result may provide insight into why PHGDH copy number gain is observed in melanoma more frequently than in most other tumor types.

scholarly journals Top-level MET gene copy number gain defines a subtype of poorly differentiated pulmonary adenocarcinomas with poor prognosis

2020 ◽  
Vol 9 (3) ◽  
pp. 603-616 ◽  
Author(s):  
Tobias Raphael Overbeck ◽  
Dana Alina Cron ◽  
Katja Schmitz ◽  
Achim Rittmeyer ◽  
Wolfgang Körber ◽  
...  
Keyword(s):  
Copy Number ◽  
Poor Prognosis ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
Gene Copy ◽  
Poorly Differentiated ◽  
Gene Copy Number Gain

Clinicopathologic Implications of ALK Gene Copy Number Gain in Non-small Cell Lung Cancer

2011 ◽  
Vol 10 (2) ◽  
pp. 87 ◽  
Author(s):  
Seol-Bong Yoo ◽  
Hyojin Kim ◽  
Xianhua Xu ◽  
Ping-Li Sun ◽  
Yan Jin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Copy Number ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
Small Cell ◽  
Gene Copy ◽  
Small Cell Lung ◽  
Gene Copy Number Gain

scholarly journals Dermal exosomes containing miR-218-5p promote hair regeneration by regulating β-catenin signaling

2020 ◽  
Vol 6 (30) ◽  
pp. eaba1685 ◽  
Author(s):  
Shiqi Hu ◽  
Zhenhua Li ◽  
Halle Lutz ◽  
Ke Huang ◽  
Teng Su ◽  
...  
Keyword(s):  
Hair Follicle ◽  
Hair Growth ◽  
Dermal Papilla ◽  
Hair Follicles ◽  
Hair Cycle ◽  
Paracrine Signaling ◽  
Hair Regrowth ◽  
Study Results ◽  
Anagen Phase ◽  
Hair Follicle Cycle

The progression in the hair follicle cycle from the telogen to the anagen phase is the key to regulating hair regrowth. Dermal papilla (DP) cells support hair growth and regulate the hair cycle. However, they gradually lose key inductive properties upon culture. DP cells can partially restore their capacity to promote hair regrowth after being subjected to spheroid culture. In this study, results revealed that DP spheroids are effective at inducing the progression of the hair follicle cycle from telogen to anagen compared with just DP cell or minoxidil treatment. Because of the importance of paracrine signaling in this process, secretome and exosomes were isolated from DP cell culture, and their therapeutic efficacies were investigated. We demonstrated that miR-218-5p was notably up-regulated in DP spheroid–derived exosomes. Western blot and immunofluorescence imaging were used to demonstrate that DP spheroid–derived exosomes up-regulated β-catenin, promoting the development of hair follicles.

scholarly journals Importance of Copy Number Alterations of FGFR1 and C-MYC Genes in Triple Negative Breast Cancer

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Milica Nedeljković ◽  
Nikola Tanić ◽  
Tatjana Dramićanin ◽  
Zorka Milovanović ◽  
Snežana Šušnjar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Marker ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Clinical Course ◽  
Copy Number Gain ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
The Impact

Summary Background: Triple negative breast cancer (TNBC) is characterized by aggressive clinical course and is unresponsive to anti-HER2 and endocrine therapy. TNBC is difficult to treat and is often lethal. Given the need to find new targets for therapy we explored clinicopathological significance of copy number gain of FGFR1 and c-MYC. Our aim was to determine the impact of FGFR1 and c-MYC copy number gain on clinical course and outcome of TNBC. Methods: FGFR1 and c-MYC gene copy number alterations were evaluated in 78 archive TNBC samples using TaqMan based quantitative real time PCR assays. Results: 50% of samples had increased c-MYC copy number. c-MYC copy number gain was associated with TNBC in contrast to ER positive cancers. Our results showed significant correlation between c-MYC copy number gain and high grade of TNBCs. This suggests that c-MYC copy number could be an useful prognostic marker for TNBC patients. c-MYC copy number gain was associated with high pTNM stage as well as lobular and medullary tumor subtypes. 43% of samples had increased FGFR1 copy number. No correlations between FGFR1 copy number gain and clinicopathological variables were observed. Conclusions: We identified c-MYC copy number gain as a prognostic marker for TNBC. Our results indicate that c- MYC may contribute to TNBC progression. We observed no significant association between c-MYC and/or FGFR1 copy number status and patient survival.

scholarly journals Genomic features and tumor immune microenvironment alteration in NSCLC treated with neoadjuvant PD-1 blockade

2022 ◽  
Vol 6 (1) ◽  
Author(s):  
Shuhang Wang ◽  
Pei Yuan ◽  
Beibei Mao ◽  
Ning Li ◽  
Jianming Ying ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Gain ◽  
Pathological Response ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Neoadjuvant Immunotherapy ◽  
Mutation Burden ◽  
Tumor Immune Microenvironment ◽  
Nsclc Patients ◽  
Insight Into

AbstractSeveral clinical trials have shown the safety and effectiveness of PD-1/PD-L1 inhibitors in neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC). However, 18–83% patients can benefit from it. In this study, we aimed to assess the association of PD-L1 expression, tumor mutation burden, copy number alteration (CNA, including copy number gain and loss) burden with the pathologic response to neoadjuvant PD-1 blockade and investigate the changes in the tumor immune microenvironment (TIME) during neoadjuvant immunotherapy in NSCLC. Pre-immunotherapy treatment tumor samples from twenty-nine NSCLC patients who received neoadjuvant immunotherapy with sintilimab, an anti-PD-1 drug, were subjected to targeted DNA sequencing and PD-L1 immunochemistry staining. The pathological response was positively correlated with tumor proportion score (TPS) of PD-L1 and negatively correlated with copy number gain (CNgain) burden. Of note, the combination of CNgain burden and TPS can better stratify major pathological response (MPR) patients than did CNgain or TPS alone. Whereas, TMB showed a limited correlation with pathological regression. Additionally, PD-1 blockade led to an increase in CD8+PD-1−T cells which was clinically relevant to MPR as evaluated by multiplex immunofluorescence. A significant reduction in CD19+ cells was observed in the Non-MPR group but not in the MPR group, indicating the involvement of B cells in improving neoadjuvant immunotherapy response in NSCLC. Together, our study provides new data for the correlation of PD-L1 expression and genomic factors with drug response in neoadjuvant immunotherapy settings in NSCLC. The changes of TIME may provide novel insight into the immune responses to neoadjuvant anti-PD-1 therapy.

scholarly journals Copy number gain of CMTM6 increases the expression of PD-L1 in undifferentiated pleomorphic sarcoma

2021 ◽  
Author(s):  
Shin Ishihara ◽  
Takeshi Iwasaki ◽  
Kenichi Kohashi ◽  
Yuichi Yamada ◽  
Yu Toda ◽  
...  
Keyword(s):  
Copy Number ◽  
Transmembrane Domain ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
The Cancer Genome Atlas ◽  
Gene Copy ◽  
Undifferentiated Pleomorphic Sarcoma ◽  
Pleomorphic Sarcoma ◽  
Number Variation ◽  
Cancer Genome Atlas

Abstract Background Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometime strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained still unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6. Materials and methods Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data. Results TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had worse prognosis for overall survival. Conclusions CMTM6 expression was significantly correlated with PD-L1 expression. CMTM6 expression induced strong PD-L1 expression (≥ 50%). CMTM6 copy number gain promoted CMTM6 expression and increased PD-L1 expression in UPS.

MYC and human telomerase gene (TERC) gene copy number gain in resected in non-small cell lung cancer (NSCLC).

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 10580-10580 ◽  
Author(s):  
A. Flacco ◽  
V. Ludovini ◽  
F. R. Tofanetti ◽  
F. Bianconi ◽  
G. Bellezza ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Copy Number ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
Small Cell ◽  
Gene Copy ◽  
Small Cell Lung ◽  
Human Telomerase ◽  
Gene Copy Number Gain

The effect of IGF-I on the growth of secondary hair follicles of the Cashmere goat in vitro

1997 ◽  
Vol 1997 ◽  
pp. 170-170
Author(s):  
H. Galbraith ◽  
D. Sims ◽  
D. Hazlerigg
Keyword(s):  
Growth Factors ◽  
Hair Follicle ◽  
Human Hair ◽  
Hair Follicles ◽  
Cashmere Goat ◽  
Igf I ◽  
Hair Follicle Cycle ◽  
Insulin Like Growth Factors

Factors regulating the growth of Cashmere fibre and the hair follicle cycle are poorly understood. Insulin-like growth factors (IGFs) or insulin at higher concentrations, have been shown to stimulate in vitro growth of human hair follicles (Philpott et al, 1994). The role of such mitogens in the production of cashmere fibre by the Cashmere goat has not been previously investigated. The objective the study reported here was to investigate the growth of hair follicles in the absence and presence of insulin or IGF-I using our established in vitro technique.

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