ABSTRACT
Cancer cells demand excess nutrients to support their proliferation, but how tumours exploit extracellular amino acids during systemic metabolic perturbations remain incompletely understood. Here, we use a Drosophila model of high-sugar diet (HSD)-enhanced tumourigenesis to uncover a systemic host-tumour metabolic circuit that supports tumour growth. We demonstrate coordinate induction of systemic muscle wasting with tumour-autonomous Yorkie-mediated SLC36-family amino acid transporter expression as a proline-scavenging programme to drive tumourigenesis. We identify Indole-3-propionic acid as an optimal amino acid derivative to rationally target the proline-dependency of tumour growth. Insights from this whole-animal Drosophila model provide a powerful approach towards the identification and therapeutic exploitation of the amino acid vulnerabilities of tumourigenesis in the context of a perturbed systemic metabolic network.
Subject(s)
Dietary Sugars/adverse effects , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiopathology , Neoplasms, Experimental/physiopathology , Proline/metabolism , Amino Acid Transport Systems/genetics , Amino Acid Transport Systems/metabolism , Animals , Animals, Genetically Modified , Carcinogenesis , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Gene Expression Profiling , Hemolymph/drug effects , Hemolymph/metabolism , Larva , Muscle Weakness/chemically induced , Muscle Weakness/pathology , Muscular Atrophy/chemically induced , Muscular Atrophy/pathology , Neoplasms, Experimental/etiology , Nuclear Proteins/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Trans-Activators/genetics , YAP-Signaling Proteins , ras Proteins/geneticsABSTRACT
The mechanisms by which prostate cancer shifts from an indolent castration-sensitive phenotype to lethal castration-resistant prostate cancer (CRPC) are poorly understood. Identification of clinically relevant genetic alterations leading to CRPC may reveal potential vulnerabilities for cancer therapy. Here we find that CUB domain-containing protein 1 (CDCP1), a transmembrane protein that acts as a substrate for SRC family kinases (SFKs), is overexpressed in a subset of CRPC. Notably, CDCP1 cooperates with the loss of the tumor suppressor gene PTEN to promote the emergence of metastatic prostate cancer. Mechanistically, we find that androgens suppress CDCP1 expression and that androgen deprivation in combination with loss of PTEN promotes the upregulation of CDCP1 and the subsequent activation of the SRC/MAPK pathway. Moreover, we demonstrate that anti-CDCP1 immunoliposomes (anti-CDCP1 ILs) loaded with chemotherapy suppress prostate cancer growth when administered in combination with enzalutamide. Thus, our study identifies CDCP1 as a powerful driver of prostate cancer progression and uncovers different potential therapeutic strategies for the treatment of metastatic prostate tumors.
