Melanoma: from Mouse Model to Metabolism.
Luo, Chi.
2013
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Abstract: Melanoma is
the deadliest form of skin cancer, because it can easily progress to metastasis even
when the primary tumor is small enough to go undetected. Once metastasis occurs,
melanoma becomes refractory to current treatment modalities. Therefore, a better
understanding of the molecular machinery controlling melanomagenesis and metastasis is
needed. Our laboratory previously created ... read morea melanocyte specific BRAFV600E transgenic
mouse model which presents a severe skin phenotype but fails to develop melanoma with
high penetrance. Here, I characterized the transgenic mouse in a pure C57BL/6 genetic
background, and further generated a simple but reliable melanoma mouse model by
combining the BRAFV600E mutation, Arf deletion and UV irradiation. My results indicate
that oncogenic BRAFV600E expression early in melanocytes can not only induce a
phenotypic switch to the Schwannian lineage but also implement DNA damage repair
mechanism by epigenetically suppressing XPC. Deletion of Arf adds another layer of
suppression on XPC transcription, making melanocytes even less capable of repairing DNA
damages instigated by both oncogenic BRAFV600E stimulation and UV irradiation, thereby
leading to melanoma development. Interestingly, the melanocytic-Schwannian lineage
switching may potentially act as a barrier for BRAFV600E to induce melanoma. Using this
mouse model and cell lines derived, I continued to study factors, including Akt isoforms
and cell cycle regulators CDK6 and cyclin D1, in various aspects of melanoma
pathogenesis. My results show that Akt1 is primarily involved in regulating melanoma
proliferation and stemness, whereas Akt3 functions mainly on melanoma migration but has
no significant effect on proliferation in vitro and tumor initiation in vivo. The
distinct functions between Akt1 and Akt3 isoforms suggest different downstream
substrates and pathways are targeted by these two kinases which share high sequences
homology, implying isoform specific inhibition should be taken into consideration when
designing Akt based therapy for melanomas. Furthermore, I also identified CDK5 and p35
as a novel regulator for melanoma maintenance. p35, an activator for the atypical
cyclin<&ndash>dependent kinase CDK5, is substantially expressed in primary
melanocytes but reduced gradually upon melanocyte transformation. Interestingly,
melanoma cell proliferation in culture is essentially unaffected by restoration of p35;
however, the p35 reexpressing cells alter their metabolism, becoming ultrasensitive to
glucose starvation. Mechanistic study showed that p35 restoration impairs both the
activation of AMPK and the inhibition of mTOR, contributing to a failure to initiate
autophagy in response to glucose deprivation. The detailed mechanism underlying p35
mediated deregulation of AMPK and mTOR is still elusive, but clearly the identification
of p35 and CDK5 in melanoma autophagy and metabolism will shed light on designing
metabolism specific treatment for melanomas. Collectively, these data provide a
promising framework for the development of novel melanoma mono or combinatorial
therapies targeting multiple cellular pathways and, the mouse model described will be a
useful system for preclinically testing the treatment modalities
developed.
Thesis (Ph.D.)--Tufts University, 2013.
Submitted to the Dept. of Genetics.
Advisor: Philip Hinds.
Committee: Grace Gill, Mark Ewen, Philip Tsichlis, and David Fisher.
Keywords: Genetics, Cellular biology, and Oncology.read less - ID:
- qb98ms408
- Component ID:
- tufts:20422
- To Cite:
- TARC Citation Guide EndNote
