Mutated Tumor Suppressors and its effects on Pancreatic Cancer

By: Sophia Rivadeneira

10th grade; Cold Spring Harbor High School

Problem

- Pancreatic cancer is a highly destructive malignancy, with only a 5 year survival rate of less than 7%

- Findings in order to apprehend mechanisms of disease progression, the generation of detection, and targeted treatment strategies are desperately needed

Hypothesis

What is the effect of tumor suppressors when mutated or deleted on tumor growth?

Experiment

By creating conditionally expressed point mutant alleles by harboring KO alleles and KI alleles of specific tumor suppressors and KRAS, we were able to see unique effects of different mutated tumor suppressors on the growth and development of cancer.

Trp53 and KRAS

- Generated a conditionally expressed point mutant allele with the activation of both KrasG12D and Trp53R172H through the interbreeding with Pdx-1-Cre transgenic mice

- Mice developed spontaneous PDAC.

- At necropsy, a large, firm, fibrotic, head-of-the-pancreas tumor was habitually seen

- We can conclude that Trp53R172H promotes the development of invasive and widely metastatic PDA initiated by KrasG12D

​

R172H

G12D

InK4a/Arf and KRAS

- Characterized mouse strains which harbored KrasG12D KI allele and InK4a/Arf KO allele

- The InK4a/Arf allele was engineered to sustain Cre-mediated excisions of exons 2 and 3 which eliminated p16 and p19 proteins

- Resulted in immortal cell growth and caused weight loss, ascites, jaundice, earlier appearance of PanIn lesions, and death through highly invasive tumors

- Concluded that InK4a/Arf locus is critical in regulating both the progression of PanIns and the development of invasive PDA

G12D

B: median survival rate= 11 weeks

C: pancreatic adenocarcinoma obstructing the common bile duct and causing dilation of the gall bladder; jaundice

​

​

​

​

​

​

​

​

​

​

​

T= tumor, D=duodenum = liver; *=gallbladder

1.27 months

Smad4/Dpc4 and Kras

- Studied the LOH of Smad4/Dpc4 in the murine pancreas and KrasG12D expression to progenitor cells of the murine pancreas

- Noticed that MCNs had developed instead of the accustomed IPMNs

- Concluded that the expression of haploinsufficient DPC4 expression in invasive adenocarcinomas causes MCNs

G12D

PTen and Kras

- Studied genetically engineered mouse models and documented cooperative interactions of Kras G12D and Pten loss in promoting metastatic PDAC

- Lead to the expansions of acinar cells, pancreatic progenitors, and formation of PDAC

- PTen deficiency cooperates with Kras to induce NFkB activity which controls the downstream cytokine pathway with accompanying robust stromal activity and immune cell infiltration with known tumor-promoting properties through the PI3K pathway

- Concluded that PTen operates as a haploinsufficient tumor suppressor to promote metastatic PDAC development

Mt41

MT39

approx. 3 weeks; insufficient pancreas function

For the Future

- Just completed in making more organoids

- Looking and organizing data for conventional use

- Studying more characterizations of mutated tumor suppressors on malignancies

- P16-P19 mouse with tumor; making organoids