MASSACHUSETTS GENERAL HOSPITAL, THE
Meta!astatic melanoma is a deadly cancer, lacking an effective therapeutic strategy. It is widely acce:ted that dysfunctions of normal homeostatic regulation of melanoblasts result in neoplastic convirsion to melanomas, while the exact molecular mechanism underlying melanoma conversion remains largely unclear. We have recently demonstrated the indispensable role of Notch signaling in the promotion of melanoblast survival. In this proposal, we aim to further translate our understanding of pro-survival role of Notch signaling into melanoma tumorigenesis. We have identified the Bnip3 gene as a novel target of Notch signaling in melanoblasts. Bnip3 is a member of the 5H3-only proapopl: otic proteins and has been implicated in the hypoxia-Induced autophagic cell death. Hypoxia adapl:atlon is thought to be critical for metastatic progression of melanoma. Therefore, we hypothesize that NOTCH signaling plays an improtant role in protecting melanoma cells from hypo:da-induced autophagic cell death, which confers hypoxia adaptation to melanoma cells and promotes melanoma metastatic spread. In this proposal, we will integrate biochemical and genetic approaches both in vitm and in vivo (i) to delineate the function of Notch signaling in the promution of melanoma survival against hypoxia-induced cell death; (ii) to define the role of Bnip3, as a novel target of Notch signaling, in the regulation of melanoblast cell death; (iii) to elucidate the functi:n of Notch signaling in promoting metastatic speread of melanoma. Our proposal will uncover a novel role of Notch signaling in promoting melanoblast survival and metastatic potential of malignant melanoma, and provide new insights into development of a novel therapeutic strategie for melanoma.
| AWARD OVERVIEW |
| Award Number |
1R01CA136622-01 |
Funding Agency |
Department of Health and Human Services |
| Total Award Amount |
$660,472 |
Project Location - City |
Boston |
| Award Date |
06/25/2009 |
Project Location - State |
MA |
| Project Status |
Completed |
Project Location - Zip |
02114-0000
|
| Jobs Reported |
0.00 |
Congressional District |
09 |
| Project Location - Country |
US |
|
|
Recipient Information
(Grants)
| Recipient Information (Grants) |
|
Recipient Name
|
MASSACHUSETTS GENERAL HOSPITAL, THE |
| Recipient DUNS Number |
073130411
|
| Recipient Address |
55 FRUIT ST |
| Recipient City |
BOSTON |
| Recipient State |
Massachusetts |
| Recipient Zip |
02114-2621 |
| Recipient Congressional District |
09 |
| Recipient Country |
USA |
Required to Report Top 5
Highly Compensated Officials |
No |
Projects and Jobs Information
| Projects and Jobs Information |
| Project Title |
Role of Notch Signaling in Regulation of Autophagy in Melanoblast and Melanoma |
| Project Status |
Completed |
| Final Project Report Submitted |
Yes |
| Project Activities Description |
General Medical and Surgical Hospitals |
| Quarterly Activities/Project Description |
We hypothesize that Notch signaling plays a role in mediating melanoma survival against hypoxia-induced autophagic cell death. To test this hypothesis, we examined effects of hypoxia in the induction of autophagy and cell death in non-metastatic melanoma cells. By employing a GFP-LC3 assay to monitor autophagy induction, we found that hypoxia treatment resulted in significant induction of autophagy and cell death in melanoma cells. Consistently, melanoma survival was significantly restored by specific inhibition of autophagy. Hence, these data suggest the involvement of autophagy in melanoma cell death in hypoxia. Next, we examined a role of Notch signaling in the regulation of hypoxia response in melanoma cells. Forced expression of a constitutive active NOTCH1 (NICD1) significantly reduced melanoma cell death under hypoxia, indicating a pro-survival function of Notch signaling in melanoma cells in hypoxia. For many cell types, cells under hypoxia should alter their energy metabolism from an aerobic to an anaerobic glycolytic pathway to adapt low oxygen tension, and failure of this alternation results in metabolic catastrophe and cell death. Therefore, we tested if Notch signaling is involved in the alteration of energy metabolism. We compared energy metabolic status between melanoma cells expressing NICD1 and control cells. In support of this hypothesis, the NICD1-melanoma cells exhibited significant upregulation of glucose consumption and lactate production. Hence these data suggest that Notch signaling plays a role in promoting the glycolysis pathway in melanoma cells. Hypoxia adaptation is a key for tumor formation in vivo. In fact, NICD1 melanoma formed significantly larger tumor than control melanoma cells in vivo. Based on these data, we concluded that tumorigenic activity of Notch signaling is, at least in part, achieved by Notch signaling mediated hypoxia adaptation of melanoma cells. |
| Jobs Created |
0.00 |
| Description of Jobs Created |
Metastatic melanoma is a deadly cancer, lacking an effective therapeutic strategy. Although recent genetic analysis of human melanomas have uncovered a number of oncogenic mutations involved in melanoma progression, it is still unclear how these genetic mutations are integrated with melanocyte inherent signaling pathways to promote malignant conversion of melanocytes. Emerging evidence suggests that signaling pathways required for normal tissue development also play key roles in tumorigenesis. As melanoma emerges within epidermal melanoblasts, it is be reasonable to speculate that both malignant melanoma and normal melanoblasts may share key properties by which their fundamental biological processes are maintained. We have previously demonstrated an indispensable role of Notch signaling in the promotion of melanoblast survival. Consistently, by performing a series immunohistochemical analysis using human melanoma tissue arrays, we have found that Notch signaling is activated in more than 65% of malignant melanomas, implying a role of Notch signaling in the regulation of malignant melanoma. Based on these findings, we hypothesize that the pro-survival function of Notch signaling also plays a fundamental role in melanoma tumorigenesis. Hence, the overall goal of this proposal is to further elucidate the role of Notch signaling in melanoma progression. We have identified the Bnip3 gene as a novel target of Notch signaling in melanoblasts. Bnip3 is a member of the BH3-only pro-apoptotic proteins. Intriguingly, Bnip3 has been recently implicated in hypoxia-induced autophagy and autophagic cell death. Hypoxia adaptation is thought to be critical for metastatic progression of melanoma. Indeed, in our preliminary studies, we found that melanoma cells underwent intensive autophagy and autophagic cell death under hypoxia, and this autophagic cell death was ameliorated by the constitutive activation of Notch signaling. By integrating these preliminary studies, we hypothesize that NOTCH signaling plays an important role in protecting melanoma cells from hypoxia-induced autophagic cell death, which confers hypoxia adaptation to melanoma cells and promotes melanoma metastatic spread. To test this hypothesis, the following three aims are proposed: Aim 1. To delineate the function of Notch signaling in promoting melanoma survival against hypoxia-induced cell death; Aim 2. To define the molecular function of Bnip3, as a novel target of Notch signaling, in the regulation of melanoma autophagy and autophagic cell death; and Aim 3. To elucidate the role of Notch signaling in the promotion of metastatic spread of melanoma cells. Our proposal will uncover a novel role of Notch signaling in the regulation of metastatic potential of melanoma cells. Such information will provide a new insight into development of therapeutic strategies for melanoma treatment. |
Purchaser Information
(Grants)
| Purchaser Information |
| Contracting Office ID |
Not Reported |
| Contracting Office Name |
Not Available |
| Contracting Office Region |
Not Available |
| TAS Major Program |
75-0850 |
| Award Information |
| Award Date |
06/25/2009 |
| Award Number |
1R01CA136622-01 |
| Order Number |
|
| Award Type |
Grants |
| Funding Agency ID |
75 |
| Funding Agency Name |
Department of Health and Human Services |
| Funding Office Name |
Not Available |
| Awarding Agency ID |
75 |
| Awarding Agency Name |
Department of Health and Human Services |
| Amount of Award |
$660,472 |
| Funds Invoiced/Received |
$639,902 |
| Expenditure Amount |
$639,902 |
| Infrastructure Expenditure Amount |
$0 |
| Infrastructure Purpose and Rationale |
Not Reported |
| Infrastructure Point of Contact Name |
Not Reported |
| Infrastructure Point of Contact Email |
Not Reported |
| Infrastructure Point of Contact Phone |
Not Reported |
| Infrastructure Point of Contact Address |
Not Reported |
| Infrastructure Point of Contact City |
Not Reported |
| Infrastructure Point of Contact State |
Not Reported |
| Infrastructure Point of Contact Zip |
Not Reported |
Product or Service Information
(Grants)
| Product or Service Information |
| Primary Activity Code |
622110 |
| Activity Description |
General Medical and Surgical Hospitals |
| Sub-Awards Information |
| Sub-awards to Organizations |
0 |
| Sub-award Amounts to Organizations |
$0 |
| Sub-Awards to Individuals |
0 |
| Sub-Award Amounts to Individuals |
$0 |
| Number of Sub-awards less than $25,000/award |
0 |
| Amount of Sub-awards less than $25,000/award |
$0 |
| Number of payments to vendors greater than $25,000 |
0 |
| Total Amount of payments to vendors greater than $25,000/award |
$0 |
| Number of payments to vendors less than $25,000/award |
684 |
| Total Amount of payments to vendors less than $25,000/award |
$132,433 |
| Location Information |
| Latitude, Longitude |
42º 21' 44",
-71º 4' 11" |
| Congressional District |
09 |
| Address 1 |
55 Fruit Street |
| Address 2 |
|
| City |
Boston |
| County |
Suffolk |
| State |
MA |
| Zip |
02114-0000 |
|
 |