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J Cancer Metastasis Treat 2020;6:5 I http://dx.doi.org/10.20517/2394-4722.2020.13 Page 17 of 38

23. The importance of sequential mutations in pancreatic tumorigenesis

Gloria Su

Columbia University Irving Medical Center, New York, NY 10032, USA.

Background and aim: Genetically engineered animal models (GEMMs) are established robust platforms
for exploring the molecular mechanisms underlying the progression of pancreatic precancerous lesions
to invasive PDA (pancreatic ductal adenocarcinoma). For example, using Pdx1-Cre to activate mutant
Kras G12D allele in the pancreas induces full spectrum of premalignant PanIN (pancreatic intraepithelial
[1]
neoplasias) lesions that can eventually progress to invasive PDA (reviewed in ). We and others have
reported that concomitant inactivation of the tumor suppressors p16, p19, p53, or TGF-β receptor type 2
(TgfβR2) can synergize with oncogenic Kras G12D in promoting the progression of the non-invasive PanINs
[1,2]
to invasive cancer in vivo . In contrast, the inactivation of Smad4 or Acvr1b in the context of mutant
Kras G12D preferentially promotes the development of pancreatic IPMNs (intraductal papillary mucinous
[1,3]
neoplasms) but not PanINs . Collectively, these data suggest that the order in which tumor-suppressor
genes are inactivated may influence the development of pancreatic tumor subtypes. To further investigate
the importance of sequential mutations in pancreatic tumorigenesis, we generated double heterozygous
+/−
Smad4 flox/+ ;p16 ;LSL-KRAS G12D;Pdx1-Cre GEMM and asked how spontaneous inactivation of the second
allele might impact the development pancreatic precancerous lesions.
+/−
Experimental procedure: Smad4 flox/+ ;p16 ;LSL-KRAS G12D;Pdx1-Cre mice were examined and characterized
+/−
+/−
in comparison to p16 ;LSL-KRAS G12D;Pdx1-Cre and Smad4 flox/+ ;p16 ;Pdx1-Cre GEMMs.
+/−
Results: Smad4 flox/+ ;p16 ;LSL-KRAS G12D;Pdx1-Cre mice shared similar medium survival and tumor
+/−
progression to p16 ;LSL-KRAS G12D;Pdx1-Cre mice (PanIN to PDA). Molecular analyses showed that
biallelic inactivation only occurred at the p16 locus in the PanINs and PDA from Smad4 flox/+ ;p16 ;LSL-
+/−
KRAS G12D;Pdx1-Cre GEMM.
Conclusion: Our results support the previous observations that the sequential inactivation of tumor-
suppressor genes in the context of oncogenic Kras G12D can dictate the development of pancreatic
precancerous lesions. More importantly, the sequential mutations observed in mice mirror those detected
in human patient specimens and thus illustrating that the order of genetic mutations is as critical as the
mutated genes themselves in influencing tumor development and progression.

REFERENCES
1. Qiu W, Su GH. Challenges and advances in mouse modeling for human pancreatic tumorigenesis and metastasis. Cancer Metastasis Rev
2013;32:83-107.
2. Qiu w, Sahin F, Iacobuzio-Donahue CA, Garcia-Carracedo D, Wang WM, et al. Disruption of p16 and activation of Kras in pancreas
increases ductal adenocarcinoma formation and metastasis in vivo. Oncotarget 2011;2:862-73.
3. Qiu W, Tang SM, Lee S, Turk AT, Sireci AN, et al. Loss of activin receptor type 1B promotes development of intraductal papillary
mucinous neoplasms in mice with activated KRAS. Gastroenterology 2016;150:218-28.e12.

24. Cyr61 promotes tip cell activity through VEGFR2-Hippo pathway in tumor angiogenesis

1
1
1
1
1
Sarala Manandhar , Uttam Ojha , Hyeonha Jang , Sun-Hee Lee , Soo-Hyun Yoon , Li Kang ,
1
1
Myo-Hyeon Park , You Mie Lee 1,2
¹BK21 Plus KNU Multi-Omics based Creative Drug Research Team.
2 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu
41566, Republic of Korea.