Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component

Abstract

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro-metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We searched for a gene signature that discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. An unbiased approach identified, amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Ka activation signature as predictive of PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3Kaselective inhibition prevented macro-metastatic evolution by hindering tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Ka inhibition altered the quantity and the species composition of the produced lipid second messenger PIP 3 , with a selective decrease of C36:2 PI-3,4,5-P 3 . Tumoural PI3Ka inactivation prevented the accumulation of protumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour cell-intrinsic PI3Ka promotes pro-metastatic features that could be pharmacologically targeted to delay macrometastatic evolution.

Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer

“…Murine PK4A-Luc (RRID:CVCL_WB21) and R211-Luc 58 cells were cultivated in DMEM GlutaMAX medium (cat. #10566016; Gibco; Thermo Fisher Scientific) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin (cat.…”

Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects

“…The SOLAR-1 phase III study led to the approval of this small molecule that can specifically inhibit p110α by the Food and Drug Administration (FDA) in 2022, recommending its use in PIK3CA-related overgrowth spectrum [ 164 , 165 ]. These promising results have encouraged the hypothesis that alpelisib can successfully treat PC as well, especially taking into consideration that the PI3Kα isoform has a major role in metastatic evolution [ 166 ]. An in vitro study performed on human and murine samples has shown that the inhibition of PI3Kα selectively reduced C36:2 PI-3,4,5-P3 and avoided macrophage accumulation.…”

Targeting PI3K Pathway in Pancreatic Ductal Adenocarcinoma: Rationale and Progress

“…An increase in the activation of the PI3K signaling is associated with poor overall survival in PDAC patients [16,17]. Other than the K-Ras-mediated activation of this signaling pathway, the presence of the oncogenic mutation in the PI3KCA gene itself is one of the known mechanisms of its hyperactivation; however, this mutation is found only in a few subsets of PDAC patients [7].…”

“…Tumor intrinsic activation of PI3K signaling, particularly PI3Kalpha, is associated with an inflammatory metastatic phenotype and leads to enhanced accumulation of protumorigenic M2 (CD206+) like macrophages in PDAC [17]. Reprogramming of TAMs towards an anti-tumorigenic M1 phenotype has been associated with increased immunogenicity and increased T cell infiltration within the TME of PDAC.…”