5196 biol special emphasis pathway in cancer. goal: provide an integrated view of cancer research...
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5196 BIOLSpecial emphasis pathway in cancer
5196 BIOLSpecial emphasis pathway in cancer
• Goal: Provide an integrated view of cancer research including basic science, translational, & clinical investigation.
• History: Founded in1989 at the request of Stan Korsmeyer. Now part of the Cancer Biology Pathway.
• Attendees: WU Students (pass/fail), Cancer Biology participants (students/postdocs), Clinical Fellows from oncology and GYN, Joint sessions with Translational Oncology Group Work-in-progress meetings.
• Make sure we have your email
5196 BIOLSpecial emphasis pathway in cancer
• Approximately 60 min will be devoted to a didactic presentation by a faculty member with interaction by the participants.
• 5-10 min break (fellows excused)
• The remaining 30 min will be used to discuss a pivotal research paper from this field, preselected by the faculty member. Outside reading (30-60 min/wk) will be required. Papers will be emailed a few days in advance.
David WilsonPediatric Hematology-Oncology
Adrenocortical tumors in childhood
Previewing themes in the Cancer Biology course
The major steroidogenic organs derive from a common pool of progenitors
GATA4GATA6
SF1
Organization of the mammalian adrenal gland
Phenotypic plasticity of adrenal steroidogenic cells
• Cell proliferation occurs in the subcapsular region.
• Cells in different zones have a common origin; their phenotype depends on environmental cues.
Clinical case 1
• CT scan demonstated a L adrenal tumor, which was completely resected.
• Pathology consistent with adrenocortical adenoma.
• Patient is now a healthy teen.
• 2-year-old boy with irritability, weight gain, and acne.
• Endocrine evaluation revealed high serum cortisol and DHEA-S levels in the setting of a low serum ACTH.
Cushingoid featuresdue to excess glucocorticoids
Clinical case 2
• Previously healthy, athletic teenager.
• 3 mo of unexplained weight gain (particularly facial and abdominal fat).
• New onset acne.
• High blood pressure.
• Endocrine evaluation reveals high serum cortisol and low serum ACTH.
Clinical case 2
• CT scan showed a large L adrenal mass.
• Pathology showed adrenocortical ca w/ LN involvement
• Despite aggressive multimodality therapy, she died in 2 yrs
Adrenocortical neoplasms
• Adenoma. 5% of people over the age of 50 have at least one small, non-functioning benign tumor (“incidentaloma”). Benign tumors that secrete hormones are uncommon.
• Adrenocortical carcinoma (ACC). These malignant tumors are rare (1 case/million/yr) but carry a poor prognosis because of their propensity to spread before detection. These are usually functional.
• The factors that account for the frequent occurrence of adenomas and the low rate of ACC have been the subject of intense investigation over the past decade.
Clinical case 3
• 3-year-old previously healthy female.
• 1-2 month history of hair loss.
• 10-15% weight loss.
• Changes in external genitalia suggestive of inappropriate sex steroid production.
• Imaging reveals adrenal gland enlargement.
Rosie
Disruption of the HPG axis leads to sex steroidogenic tumor formation
Alopecia reflects ectopic sex steroid production by gonadal-like neoplastic cells in the adrenal
A developmental model of altered cell fate
Gata4
Adrenocortical neoplasia in other species
Potential models for understanding adrenocortical neoplasia
Post-gonadectomy adrenocortical metaplasia/neoplasia in the mouse
• Strain dependent; complex trait.
• Parabiosis and transplantation experiments suggest that chronic LH stimulation is key (seasonal baldness) and that susceptibility resides in the adrenal gland.
• Ectopic expression of the gonadal-like marker Gata4 heralds the GDX-induced phenotypic switch.
Gata4
Hypothesis: a multipotential stem/progenitor cell gives rise to both corticoid- and sex steroid-producing cells
Gata4 haploinsufficiency attenuates GDX-induced adrenocortical neoplasia in B6D2F1 mice
Gata4 haploinsufficiency abrogates adrenocorticalestrogen & androgen production in GDX mice
Do clonal preexisting epigenetic changes impact the ability of stem cells to respond to LH?
Laser capture microdissection of neoplastic adrenocortical tissue from GDX inbred mice
Genome-wide methylation analysis workflowMaxim Schillebeeckx & Rob Mitra
Genes showing differential methylation were subjectedto a secondary screen of qRT-PCR
Genes exhibiting differential methylation (within 1 kB of the transcription start site)
Gene Function% methylation in
normal tissue% methylation inneoplastic tissue
Wdr63 Protein-protein interactions 51 + 4 24 + 2
Tcf21 Transcription factor 76 + 5 46 + 2
Foxs1 Transcription factor 76 + 7 38 + 1
Galr2 Galanin receptor type 2 56 + 4 24 + 6
Angptl2 Angiopoietin related protein 82 + 4 50 + 4
Igfbp6 IGF-II binding protein 79 + 8 42 + 8
Tinagl1 Adrenocortical zonation 26 + 1 62 + 9
qRT-PCR analysis of differentially methylated genes in LCM samples
IHC of Igfbp6 in adrenals of OVX inbred mice
A
Summary
• Adrenocortical neoplasms are common in humans. The factors that account for the frequent occurrence of adenomas and the low rate of ACC are unknown.
• There are naturally-occurring and genetically-engineered animal models of adrenocortical neoplasia..
• Key themes emerge (germline vs. somatic mutations, crosstalk between epithelia and stroma, epigenetic regulation of stem cells)
Theme 1:
Germline vs. somatic mutations
Prevalence of adrenocortical neoplasms in children
girls
boys
case 1
case 2
Germline vs. acquired mutations?
TP53 R337H mutation and childhood adrenocortical tumors in Brazil
TP53 R337H mutation and childhood adrenocortical tumors in Brazil
Hypothesis: other (more subtle) germline variants contribute to pediatric cases of ACC and other cancers
Germline vs. somatic mutations leading to cancer
New data on germline mutations in pediatric leukemia
Landmark research on somatic mutations in AML
Breakthroughs in sequencing technology
Todd Druley John Welch Rob Mitra
Theme 2:
Crosstalk between epithelial cells and stroma:the importance of signaling molecules to tumorigenesis
Prevalence of adrenocortical neoplasms in humans parallels that of brain tumors
David Gutmann Josh Rubin
What genetic, developmental, and anatomical factors impact tumorigenesis in children vs. adults?
What are the key signals between tumor and stroma?
What is the mechanistic basis for gender differences in tumor formation?
Theme 3:
Aberrant stem cell maintenance or differentiation impacts tumorigenesis
WNT/-catenin signaling has been implicated in adrenocortical stem cell maintenance & in tumorigenesis
Epigenetic alterations at the IGF2 locus are common in adrenocortical carcinoma
Epigenetic alterations at the IGF2 locus drive stem cell proliferation and inhibit differentiation/apoptosis
Evidence supporting two conceptual models of adrenocortical neoplasia
Epigenetic regulation of cancer stem cells
Dan LinkGrant Challen Jackie Payton
ACC is not readily cured by chemotherapy, so novel treatments are needed
New therapies for the treatment of cancer
Brian van TineNancy Bartlett
Novel therapeutic targets
Trop2, an oncogenic cell surface protein, is commonly over-expressed in several epithelial tumor types
Loren Michel
DNA and RNA surveillance mechanisms in cancer
Zhongsheng You
Students’ invited speaker
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