Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely due to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology 1 , 2 . The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumourigenesis and drug resistance 3 – 7 . Moreover, PSC activation occurs very early during PDAC tumourigenesis 8 – 10 , and activated PSCs comprise a significant fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an Achilles’ heel exploitable to develop effective strategies for PDAC therapy and diagnosis. Here, starting with systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion significantly slow tumour progression and augment chemotherapy efficacy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and EMT status. Moreover, we show that, consistently in both mouse models and human PDAC, aberrant production of LIF in the pancreas is unique to pathological conditions and correlates with PDAC pathogenesis, and circulating LIF level changes correlate well with tumour response to therapy. Collectively, these findings uncover a previously unappreciated function of LIF in PDAC tumourigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. These studies underscore how a better understanding of cell-cell communications within the tumour microenvironment promotes novel strategies for cancer therapy.
Signaling complexes are often organized in a spatiotemporal manner and on a minute timescale. Proximity labeling based on engineered ascorbate peroxidase APEX2 pioneered in situ capture of spatiotemporal membrane protein complexes in living cells, but its application to cytosolic proteins remains limited due to the high labeling background. Here, we develop proximity labeling probes with increased labeling selectivity. These probes, in combination with label-free quantitative proteomics, allow exploring cytosolic protein assemblies such as phosphotyrosine-mediated protein complexes formed in response to minute-scale EGF stimulation. As proof-of-concept, we systematically profile the spatiotemporal interactome of the EGFR signaling component STS1. For STS1 core complexes, our proximity proteomics approach shows comparable performance to affinity purification-mass spectrometry-based temporal interactome profiling, while also capturing additional—especially endosomally-located—protein complexes. In summary, we provide a generic approach for exploring the interactome of mobile cytosolic proteins in living cells at a temporal resolution of minutes.
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