Open AccessSHP2 regulates adipose maintenance and adipocyte‐pancreatic cancer cell crosstalk via PDHA1
Author(s) -
Olou Appolinaire A.,
Ambrose Joe,
Jack Jarrid L.,
Walsh McKin,
Ruckert Mariana T.,
Eades Austin E.,
Bye Bailey A.,
Dandawate Prasad,
VanSaun Michael N.
Publication year - 2023
Publication title -
journal of cell communication and signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 44
eISSN - 1873-961X
pISSN - 1873-9601
DOI - 10.1007/s12079-022-00691-1
Subject(s) - adipocyte , adipose tissue , crosstalk , endocrinology , medicine , microbiology and biotechnology , biology , chemistry , cancer research , physics , optics
Adipocytes are the most abundant cell type in the adipose tissue, and their dysfunction is a significant driver of obesity‐related pathologies, such as cancer. The mechanisms that (1) drive the maintenance and secretory activity of adipocytes and (2) mediate the cancer cellular response to the adipocyte‐derived factors are not fully understood. To address that gap of knowledge, we investigated how alterations in Src homology region 2‐containing protein (SHP2) activity affect adipocyte function and tumor crosstalk. We found that phospho‐SHP2 levels are elevated in adipose tissue of obese mice, obese patients, and differentiating adipocytes. Immunofluorescence and immunoprecipitation analyses as well as in‐silico protein–protein interaction modeling demonstrated that SHP2 associates with PDHA1, and that a positive association promotes a reactive oxygen species (ROS)‐driven adipogenic program. Accordingly, this SHP2‐PDHA1‐ROS regulatory axis was crucial for adipocyte maintenance and secretion of interleukin‐6 (IL‐6), a key cancer‐promoting cytokine. Mature adipocytes treated with an inhibitor for SHP2, PDHA1, or ROS exhibited an increased level of pro‐lipolytic and thermogenic proteins, corresponding to an increased glycerol release, but a suppression of secreted IL‐6. A functional analysis of adipocyte‐cancer cell crosstalk demonstrated a decreased migration, invasion, and a slight suppression of cell cycling, corresponding to a reduced growth of pancreatic cancer cells exposed to conditioned media (CM) from mature adipocytes previously treated with inhibitors for SHP2/PDHA1/ROS. Importantly, PDAC cell growth stimulation in response to adipocyte CM correlated with PDHA1 induction but was suppressed by a PDHA1 inhibitor. The data point to a novel role for (1) SHP2‐PDHA1‐ROS in adipocyte maintenance and secretory activity and (2) PDHA1 as a regulator of the pancreatic cancer cells response to adipocyte‐derived factors.