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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