In vivo functional dissection of a context-dependent role for Hif1α in pancreatic tumorigenesis

Abstract

Hypoxia-inducible factor 1α (Hif1α) is a key regulator of cellular adaptation and survival under hypoxic conditions. In pancreatic ductal adenocarcinoma (PDAC), it has been recently shown that genetic ablation of Hif1α accelerates tumour development by promoting tumour-supportive inflammation in mice, questioning its role as the key downstream target of many oncogenic signals of PDAC. Likely, Hif1α has a context-dependent role in pancreatic tumorigenesis. To further analyse this, murine PDAC cell lines with reduced Hif1α expression were generated using shRNA transfection. Cells were transplanted into wild-type mice through orthotopic or portal vein injection in order to test the in vivo function of Hif1α in two major tumour-associated biological scenarios: primary tumour growth and remote colonization/metastasis. Although Hif1α protects PDAC cells from stress-induced cell deaths in both scenarios—in line with the general function Hif1α—its depletion leads to different oncogenic consequences. Hif1α depletion results in rapid tumour growth with marked hypoxia-induced cell death, which potentially leads to a persistent tumour-sustaining inflammatory response. However, it simultaneously reduces tumour colonization and hepatic metastases by increasing the susceptibility to anoikis induced by anchorage-independent conditions. Taken together, the role of Hif1α in pancreatic tumorigenesis is context-dependent. Clinical trials of Hif1α inhibitors need to take this into account, targeting the appropriate scenario, for example palliative vs adjuvant therapy.

Glycemic Variability Promotes Both Local Invasion and Metastatic Colonization by Pancreatic Ductal Adenocarcinoma

“…Previously, we characterized a highly metastatic mouse model of PDAC that was driven by one allele loss of tuberous sclerosis 1 together with pancreas-specific oncogenic Kras G12D expression ( p48 Cre ; Kras G12D/+ ; Tsc1 -/+ ). 18 , 19 , 20 A particular signature of "Mek/Erk-mTOR" was identified by using cancer cell lines from those animals. The Kyoto Encyclopedia of Genes and Genomes pathway analysis of this signature uncovered the glucose-related metabolism as the major enriched pathway.…”

ALDH1A3 Accelerates Pancreatic Cancer Metastasis by Promoting Glucose Metabolism

“…Previously, we generated a number of PDAC entities with different potency of aggressiveness by using a set of transgenic mouse models (5)(6)(7)(8)(9). Notably, in the context of Tsc1 haploinsufficiency, Kras G12D preferably activated mTOR signaling via the Mek/Erk cascade, contributing to a PDAC subtype with high-metastasis potential (8).…”

“…A variety of molecular subtypes with distinctive tumor biology seem to exist (4), thus it is an unmet need to subclassify PDAC into clinically relevant subtypes and subsequently to develop targeted therapies accordingly. In this regard, we previously used a reverse-translational approach to define PDAC subtypes in mice (5)(6)(7)(8)(9) and generated several novel transgenic mouse models of PDAC entities with different potency of aggressiveness. Detailed analyses revealed that metastasis was driven by the Kras G12D /Mek/mTOR signaling axis, for which ALDH1A3 (aldehyde dehydrogenase family 1, subfamily A3) constituted a specific marker (8).…”

Efficacy of Shikonin against Esophageal Cancer Cells and its possible mechanisms in vitro and in vivo

“…HIF-1 activity in tumors depends on availability of the HIF-1a subunit, the levels of which increase under hypoxic conditions and through activation of oncogenes and/or inactivation of tumor suppressor genes. HIF1α 6 , 7 is required for hypoxia-induced cell cycle arrest, the mechanism that the enhancing stability of HIF-1α protein regulated cyclinD1 expression under hypoxia condition. HIF-1α 8 induced G0/G1 phase arrest may account for the resistance of cancer cells to some certain chemotherapeutic agents that target DNA synthesis in S phase.…”