Concerted cell and in vivo screen for pancreatic ductal adenocarcinoma (PDA) chemotherapeutics

Somayeh Layeghi-Ghalehsoukhteh, Shreoshi Pal Choudhuri, Ozhan Ocal, Yalda Zolghadri, Victor Pashkov, Hanspeter Niederstrasser, Bruce A. Posner, Havish S. Kantheti, Ana C. Azevedo-Pouly, Huocong Huang, Luc Girard, Raymond J. MacDonald, Rolf A. Brekken, Thomas M. Wilkie

Research output: Contribution to journalArticlepeer-review

Abstract

PDA is a major cause of US cancer-related deaths. Oncogenic Kras presents in 90% of human PDAs. Kras mutations occur early in pre-neoplastic lesions but are insufficient to cause PDA. Other contributing factors early in disease progression include chronic pancreatitis, alterations in epigenetic regulators, and tumor suppressor gene mutation. GPCRs activate heterotrimeric G-proteins that stimulate intracellular calcium and oncogenic Kras signaling, thereby promoting pancreatitis and progression to PDA. By contrast, Rgs proteins inhibit Gi/q-coupled GPCRs to negatively regulate PDA progression. Rgs16::GFP is expressed in response to caerulein-induced acinar cell dedifferentiation, early neoplasia, and throughout PDA progression. In genetically engineered mouse models of PDA, Rgs16::GFP is useful for pre-clinical rapid in vivo validation of novel chemotherapeutics targeting early lesions in patients following successful resection or at high risk for progressing to PDA. Cultured primary PDA cells express Rgs16::GFP in response to cytotoxic drugs. A histone deacetylase inhibitor, TSA, stimulated Rgs16::GFP expression in PDA primary cells, potentiated gemcitabine and JQ1 cytotoxicity in cell culture, and Gem + TSA + JQ1 inhibited tumor initiation and progression in vivo. Here we establish the use of Rgs16::GFP expression for testing drug combinations in cell culture and validation of best candidates in our rapid in vivo screen.

Original languageEnglish (US)
Article number20662
JournalScientific reports
Volume10
Issue number1
DOIs
StatePublished - Dec 2020

ASJC Scopus subject areas

  • General

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