Wnt signaling in senescence, nevogenesis and melanomagenesis

衰老、新生和黑色素瘤发生中的 Wnt 信号传导

• 批准号: MR/M000605/1
• 负责人: Peter Adams
• 金额: $ 56.77万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM000605%2F1
• 关键词: Wnt; signaling; senescence; nevogenesis; melanomagenesis

In 2010 in the US, there were approximately 68,000 new cases of melanoma and about 8,700 deaths from this disease (www.cancer.org). In the UK, the incidence of melanoma has increased more than any other cancer in the last 25 years (http://www.cancerhelp.org.uk/). Despite recent advances in targeted melanoma therapies (for example, vemurafenib) the prognosis for advanced melanoma remains dismal. The new generation of targeted therapies provide a significant, but modest, prolonged survival. However, drug resistance and disease progression invariably occurs. Consequently, there is an urgent need for better ways to combat this disease, perhaps focused on much earlier risk assessment and chemoprevention. Melanoma results from transformation and uncontrolled growth of melanocytes, pigment producing cells in the skin, hair and eyes. The earliest apparent melanocytic neoplasms are normal benign nevi (moles), which result from clonal proliferative expansion of oncogene-expressing melanocytes in the skin. Although the vast majority of benign human nevi do not progress to melanoma, approximately 25% of melanoma are thought to result from a pre-existing nevus. Understanding the progression of nevi to melanoma is critical to understanding the origins of melanoma. Most nevi are thought to be prevented from progression to melanoma by a process called cellular senescence - an irreversible proliferation arrest that prevents proliferation of potentially cancerous cells. In this application, we will better define the molecular status of nevus melanocytes. By doing so, we will inform on the origins of melanoma, whether from nevus or non-nevus melanocytes. This application can lead to biomarkers for melanoma risk assessment in nevi and strategies for melanoma chemoprevention. For example, one minimally invasive approach to reduce incidence of melanoma in later life might be local topical application of specific inhibitors to developing nevi in childhood and adolescence, when most acquired nevi form.

2010 年，美国约有 68,000 例黑色素瘤新病例，约 8,700 人死于该病 (www.cancer.org)。在英国，过去 25 年中黑色素瘤的发病率增幅超过任何其他癌症 (http://www.cancerhelp.org.uk/)。尽管靶向黑色素瘤治疗（例如维莫非尼）最近取得了进展，但晚期黑色素瘤的预后仍然令人沮丧。新一代靶向治疗可显着但适度地延长生存期。然而，耐药性和疾病进展总是会发生。因此，迫切需要更好的方法来对抗这种疾病，或许侧重于更早的风险评估和化学预防。黑色素瘤是由黑色素细胞（皮肤、头发和眼睛中的色素产生细胞）的转化和不受控制的生长引起的。最早的明显黑素细胞肿瘤是正常的良性痣（痣），它是皮肤中表达癌基因的黑素细胞克隆增殖性扩张的结果。尽管绝大多数良性人类痣不会进展为黑色素瘤，但大约 25% 的黑色素瘤被认为是由先前存在的痣引起的。了解痣向黑色素瘤的进展对于了解黑色素瘤的起源至关重要。大多数痣被认为可以通过一种称为细胞衰老的过程来防止进展为黑色素瘤，这是一种不可逆的增殖停滞，可以防止潜在癌细胞的增殖。在此应用中，我们将更好地定义痣黑素细胞的分子状态。通过这样做，我们将了解黑色素瘤的起源，无论是来自痣还是非痣黑素细胞。该应用可以产生用于痣黑色素瘤风险评估的生物标志物和黑色素瘤化学预防策略。例如，一种减少晚年黑色素瘤发病率的微创方法可能是局部局部应用特定抑制剂来抑制儿童和青春期痣的形成，而大多数后天性痣都是在这个时期形成的。

项目成果

Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling.

• DOI: 10.1038/jid.2015.114
• 发表时间: 2015-08
• 期刊: The Journal of investigative dermatology
• 作者: Pawlikowski JS;Brock C;Chen SC;Al-Olabi L;Nixon C;McGregor F;Paine S;Chanudet E;Lambie W;Holmes WM;Mullin JM;Richmond A;Wu H;Blyth K;King A;Kinsler VA;Adams PD
• 通讯作者: Adams PD

Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer.

• DOI: 10.1016/j.stem.2015.05.002
• 发表时间: 2015-06-04
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Adams PD;Jasper H;Rudolph KL
• 通讯作者: Rudolph KL