Marc Hansen, Ph.D.
 Investigator,
Center for Molecular Medicine
Professor of Medicine
Email: mhansen@nso2.uchc.edu
Phone: 860-679-2261
Fax: 860-679-7639
Research Interests
My laboratory is interested in the discovery and analysis of
genetic pathways involved in the etiology of two diseases,
osteosarcoma and Paget Disease of Bone. Based on phenotypic
differences there is strong evidence that primary
osteosarcoma of the appendicular skeleton and primary
osteosarcoma of the craniofacial skeleton represent separate
and distinct diseases. Allelotype analysis identified 13
chromosomal arms with significantly different frequencies of
tumor-specific loss of constitutional heterozygosity (LoH)
with eight chromosomal arms showed greater frequency of LoH
in craniofacial osteosarcoma and five showed greater
frequency of LoH in appendicular osteosarcomas. Comparative
microarray analysis of craniofacial and appendicular
osteosarcomas also revealed significantly different patterns
of genomic expression patterns in the two types of
osteosarcoma. It is possible that the phenotypic differences
between craniofacial and appendicular osteosarcoma are in
part due to the differences in the development derivation of
the cells from which they originate. By examining the
underlying genetic basis for craniofacial osteosarcoma and
contrasting it with what is known of the genetic etiology of
appendicular osteosarcoma, we may gain insight into
tumorigenic pathways that unite or separate these two bone
tumors of distinct embryonic origin.
Paget’s Disease of Bone (PDB) is a focal disorder of bone
remodeling that leads to overgrowth of affected bone, which
in rare cases progresses to osteosarcoma. It is the second
most common metabolic bone disease after osteoporosis. Two
predisposing factors have been identified in PDB: 1) Studies
of the association of measles virus or other paramyxoviruses
with PDB have implicated expression of the measles virus
nucleocapsid protein (MVNP) in the development of the
pagetic phenotype and 2) Studies of the genetics of familial
PDB that have identified a number of predisposing loci, with
approximately 40% of the familial cases linked to the
Sequestosome 1 (SQSTM1) gene on human chromosome 5q35. Our
hypothesis is that PDB arises as the result of a combination
of somatic mutations and environmental events that give rise
to the pagetic lesion. We have chosen to focus on the
genetic events that give rise to sporadic PDB and the
potential role of somatic mutation in the affected tissues
of patients to see if there is a progression of genetic
events that give rise to PDB. We are now testing the subset
of cells that contain the SQSTM1 mutation to see whether
they act to recruit normal bone cells to the pagetic lesion
and whether the osteosarcomas that arise within the pagetic
bone arise from this subset of cells or whether the tumors
arise simply as a result of increased bone turnover
activity.
Finally, we are examining the role of a tumor suppressor
gene initially discovered in our screen of osteosarcoma
tumors in the development of acquired resistance to the
cancer drug Trastuzumab (Herceptin®) in women with advanced
breast cancer. We found that in a majority of osteosarcomas
there was a correlation between absence of expression of
VPS4B and overexpression of erbB2 and EGFR in primary
osteosarcoma tumors. This accumulation of EGFR and other
receptors appears to be due to inhibition of both recycling
of the activated receptors to the plasma membrane and
degradation of the receptors via transport to the lysosomes
and leads to prolonged signaling by the activated receptors.
This internal accumulation of activated growth factor
receptors may have implications for therapeutic strategies,
as many new drugs targeted against growth factor receptors
in cancer cells either depend on access to the target at the
cell surface, or in some cases act through targeting the
activated receptor to the endosomal degradative pathway. The
determination of alternative genetic mechanisms by which
breast cancer cells develop resistance to Herceptin® and
strategies with which to treat these resistant newly tumors
has the potential to have an impact on a significant
fraction of women with breast cancer.
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