ROLE OF TGF-BETA SIGNALING IN PIK3CA-

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1 ROLE OF TGF-BETA SIGNALING IN - DRIVEN HEAD AND NECK CANCER INVASION AND METASTASIS 1,2 Sophia Bornstein, 3 Jingping Shen, 3 Jacob Minor, 3 Frank Hall, 3 Fang Zhang, 4 Sherif Said, 4 Xiao-Jing Wang, 1 Neil Gross, 3 John Song, 5 Natalie Serkova, 3 Shi- Long Lu ine/sophiabornstein.cfm Principal Investigator: Shi-Long.Lu@ucdenver.edu Departments of 1 Otolaryngology, 2 Radiation Oncology, Oregon Health & Science University, Departments of 3 Otolaryngology, 4 Pathology and 5 Anesthesiology, University of Colorado Denver *No conflicts of interest to disclose

2 Introduction PI3K pathway alterations (, PTEN, AKT) are common in solid tumors and are highly linked to oncogenesis in multiple tumor types including HNSCC. -Gene amplification of ~40%, gain-of-function mutation~10% PI3K pathway inhibitors are currently being investigated pre-clinically as targeted therapies for HNSCC. While the PI3K pathway has been linked to proliferation and survival, the role of this pathway in invasion and metastasis is unclear. We aimed to investigate the in vivo role of PI3K pathway alterations in HNSCC initiation and progression to more specifically guide targeted therapy approaches.

3 Overexpression of increases susceptibility to 4NQOinduced HNSCC carcinogenesis 4NQO 1 6m 12m RU486 Incidence of HNSCC control 5-6 m (visual) m (patho) 2/25 (8%) 9/23 (39%)* 21/25 (84%) 20/23 (87%) *p<0.05

4 High incidence of poorly differentiated tumors and metastasis in tumors A. Control Tongue B. 100% Poorly Mod Well CIS C. PET scan MRI 80% 60% 40% 20% 0% Control (n=21) (n=20) LN Lung Metastasis at 10-12m: :=8/20 (40%) control: 0/18

5 Potential molecular mechanisms mediating -induced HNSCC progression control pakt473 pakt308 PDK1 actin

6 PDK1 (PHOSPHOINOSITIDE-DEPENDENT KINASE) PIP2 p85 p110 PTEN PIP3 mtorc2 PDK1 S473 AKT T308 AKT independent signaling PDK1 is amplified in breast cancer and down-regulation of PDK1 inhibits migration and metastasis in breast cancers Controls migration but not cell growth and proliferation in lymphocytes Role of PDK1 in HNSCC is unclear, and further studies are ongoing.

7 , PDK1 and pakt in human HNSCC pakt PDK1 PDK1 pakt Well/mod n=39 Poor n=21 Mets n=18 0% 20% 40% 60% 80% 100% % of samples with 2+ staining Poor/mets vs. well/mod SCC: p<0.01

8 How does PDK1 contribute to HNSCC invasion and metastasis? A. B. TGFβ1 protein level (pg/mg) 600 p<0.05 TGFβ1 ELISA 500 p< control control Tumor tissues Tumor cells control psmad3 Actin

9 Potential mechanism of in HNSCC progression Epithelia PIP2 Stroma pakt p85 PI3K p110 PIP3 PDK1? TGFβ1 TGFβ1 Smad3 Proliferation Growth Apoptosis EMT, Inflammation, Angiogenesis Initiation Invasion & Metastasis

10 Conclusions PI3K pathway alterations are common and promote HNSCC progression in vivo. Overexpression of, the catalytic subunit of PI3K, is associated with poor differentiation and metastasis in our mouse model and in human HNSCC. mediated HNSCC appears to be mediated by AKT-independent signaling, particularly through activation/overexpression of PDK1. Further characterization of alterations in AKT-independent PI3K targets including PDK1 may lead to novel targeting of HNSCC progression. -Personalized and stage specific pathway targeting -Radiosensitization

11 Acknowledgments Radiation Medicine Oregon Health & Science University ABR Holman Research Pathway Charles R Thomas MD Shi-Long Lu Lab (UCD): Jingping Shen Jacob Minor Fang Zhang Matthew Whinery Li Du Francis Hall Xi Chen Collaborators: Neil Gross (OHSU) Molly Kulesz-Martin (OHSU) Xiao-Jing Wang (UCD) John Song (UCD) Antonio Jimeno (UCD) Sherif Said (UCD) Natalie Serkova (UCD) Biostatistical Core (UCD) Grant Support: NIDCR/NIH R01 Thyroid, Head and Neck (THANC) foundation American Cancer Society Colorado Cancer League University of Colorado Cancer Center

12 PI3K alterations in HNSCC Focus on p85 p110 PIP2 PTEN encodes for p110α, the catalytic subunit of PI3K, which is the most commonly mutated oncogene in solid tumors after RAS. PIP3 AKT mutations are correlated with tumor initiation, progression, and metastasis in lung SCC, esophageal SCC, and breast cancer; and poor prognosis and recurrence in colon cancer. Simplified version of the PI3K pathway In HNSCC: Gene amplification of ~40%, gain-of-function mutation~10% overexpression has been correlated with advanced stage, vascular invasion, and lymph node metastasis.

13 Generation and Characterization of an inducible, head-and-neck specific genetically engineered mouse model (-GEMM) transactivator target Keratin 5 GAL4 PR-LBD p65 GAL4 tata K5.GLp65 tata. X RU GEMM overexpression in oral epithelium

14 Overexpression of resulted in head and neck epithelial hyperplasia/carcinoma in situ Buccal mucosa Tongue control 1 year observation

15 Epithelial Mesenchymal Transition (EMT) and overexpression of Twist in tumors Control E-cad/Vimentin E-cad/Vimentin 120 control Relative expression (qrt-pcr) p<0.01 Twist downregulates E-Cadherin and promotes EMT

16 Ex Vivo Cells from the tumors are more fibroblast-like control and invasive BD matrigel invasion chamber at 48 hours

17 Journal of Clinical Investigation, 2009

Overexpression of PIK3CA in murine head and neck epithelium drives tumor invasion and metastasis through PDK1 and enhanced TGFβ signaling

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