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Genome-wide CRISPR Screen Reveals Regulators of PI3K Inhibitor Resistance in Pancreatic Ductal Adenocarcinoma.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Genome-wide CRISPR Screen Reveals Regulators of PI3K Inhibitor Resistance in Pancreatic Ductal Adenocarcinoma.
Author:	Han, Han.
Published:	Ann Arbor : ProQuest Dissertations & Theses, 2023
Description:	130 p.
Notes:	Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
Notes:	Advisor: Lin, Richard Z.
Contained By:	Dissertations Abstracts International85-03B.
Subject:	Biology.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30310979
ISBN:	9798380367875

Genome-wide CRISPR Screen Reveals Regulators of PI3K Inhibitor Resistance in Pancreatic Ductal Adenocarcinoma.
Han, Han.

Genome-wide CRISPR Screen Reveals Regulators of PI3K Inhibitor Resistance in Pancreatic Ductal Adenocarcinoma. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 130 p.

Source: Dissertations Abstracts International, Volume: 85-03, Section: B.

Thesis (Ph.D.)--State University of New York at Stony Brook, 2023.

This item must not be sold to any third party vendors.

Pancreatic ductal adenocarcinomas (PDACs) are resistant to systemic treatments including immunotherapy. Over 90% of PDACs have oncogenic KRAS mutations, and phosphoinositide 3- kinases (PI3Ks) are direct effectors of KRAS. Previously, we demonstrated that genetic ablation of PI3K isoform, Pik3ca in the KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cell line induced complete tumor elimination by infiltrating T cells in a mouse model. However, clinical trials using PI3K inhibitors for PDAC patients exhibited limited efficacy due to drug resistance. To identify potential contributors to PI3K inhibitor resistance, we conducted an in vivo genome-wide gene-deletion screen using the Pik3ca-/- KPC (αKO) cells implanted in the mouse pancreas and identified propionyl-CoA carboxylase subunit B (PCCB) modulates PIK3CA-mediated immune evasion. Deletion of Pccb gene in αKO cells (named p-αKO) allowed tumor progression causing death of host mice even though p-αKO tumors are infiltrated with T cells. Single-cell RNA sequencing revealed that infiltrating clonally expanded T cells in p-αKO tumors were more exhausted as compared to T cells founds in αKO tumors. Blockade of PD-L1/PD1 interaction reversed T cell exhaustion, slowed tumor growth and improved the survival of mice implanted with p-αKO cells. These results indicate that propionyl-CoA carboxylase activity can modulate PIK3CA-regulated immune surveillance of PDAC.

ISBN: 9798380367875Subjects--Topical Terms:

188667
Biology.
Subjects--Index Terms:

CRISPR screen

Genome-wide CRISPR Screen Reveals Regulators of PI3K Inhibitor Resistance in Pancreatic Ductal Adenocarcinoma.
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