Abstract
Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures. The anti-CSC mechanism of action of this specific chemical series was found to rely on induction of lysosomal membrane permeabilization (LMP), which is likely associated with the increased lysosomal mass observed in PaCSCs. Using the well characterized LMP-inducer siramesine as a tool molecule, we show elimination of the PaCSC population in mice implanted with tumors from two PDX models. Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC.
Highlights
It is generally accepted that the majority of solid tumors contain a small sub-population of highly plastic, tumorigenic and chemoresistant cells, known as cancer stem cells (CSCs) or cancer-initiating cells, which are the drivers of tumor evolution, metastasis and tumor relapse [1,2].from a clinical perspective, targeting and eliminating the compromise stem cell (CSC) compartment would ensure a more effective tumor eradication [2,3,4,5]; to date, only a handful of therapeutics targeting CSCs have advanced to clinical trials
Following 30-hour treatment with 5 μM of each compound, we assessed mousethat embryonic stemcancer cells (mESCs) viability by a standard MTS assay and identified 12 compounds that decreased the number of viable cells by at least 50%, belonging to 2 classes (Figure 1A,B)
The role of the PI3K/mammalian target of rapamycin (mTOR) pathway in both mESC and CSC biology is well described [21,22,23,24,25,26] and, the identification of these compounds validates the effectiveness of the screen
Summary
It is generally accepted that the majority of solid tumors contain a small sub-population of highly plastic, tumorigenic and chemoresistant cells, known as cancer stem cells (CSCs) or cancer-initiating cells, which are the drivers of tumor evolution, metastasis and tumor relapse [1,2].from a clinical perspective, targeting and eliminating the CSC compartment would ensure a more effective tumor eradication [2,3,4,5]; to date, only a handful of therapeutics targeting CSCs have advanced to clinical trials (reviewed in Saygin et al [6]). The use of markers expressed on the cell surface of CSCs, side-population or intracellular enzymatic activities (e.g., ALDH1 activity) have been used to isolate and enrich for CSCs, but these methods are limited due to 1) the lack of clearly defined CSC-specific markers 2) CSC phenotypic heterogeneity, 3) the propensity of enriched CSCs to undergo asymmetric division to restore the original cellular distribution of CSCs and non-CSCs prior to enrichment (i.e., CSC plasticity), and 4) the technical limitation of isolating large numbers of highly purified CSC populations. Long-term cultures of purified CSCs isolated based on the expression of cell surface markers or enzymatic activity are technically unsustainable and not amenable to compound screening. Alternative phenotypic/functional approaches based on methodologies such as in vitro sphere cultures have been utilized, but such approaches are labor-intensive, the heterogeneity of the cultures cannot be controlled for, and spheres are inherently difficult to manipulate making this approach very low-throughput
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