Papers by Frédéric Hollande
Subpopulations of cancer stem–like cells (CSC) are thought to drive tumor progression and posttre... more Subpopulations of cancer stem–like cells (CSC) are thought to drive tumor progression and posttreatment recurrence in multiple solid tumors. However, the mechanisms that maintain stable proportions of self-renewing CSC within heterogeneous tumors under homeostatic conditions remain poorly understood. Progastrin is a secreted peptide that exhibits tumor-forming potential in colorectal cancer, where it regulates pathways known to modulate colon CSC behaviors. In this study, we investigated the role of progastrin in regulating CSC phenotype in advanced colorectal cancer. Progastrin expression and secretion were highly enriched in colon CSC isolated from human colorectal cancer cell lines and colon tumor biopsies. Progastrin expression promoted CSC self-renewal and survival, whereas its depletion by RNA interference–mediated or antibody-mediated strategies altered the homeostatic proportions of CSC cells within heterogeneous colorectal cancer tumors. Progastrin downregulation also decreased the frequency of ALDHhigh cells, impairing their tumor-initiating potential, and inhibited the high glycolytic activity of ALDHhigh CSC to limit their self-renewal capability. Taken together, our results show how colorectal CSC maintain their tumor-initiating and self-renewal capabilities by secreting progastrin, thereby contributing to the tumor microenvironment to support malignancy. Cancer Res; 76(12); 3618–28. ©2016 AACR.
Legend for Supplemental Figures S1-S6.
Official gene symbols (HGNC) for our 20 NK signature genes and a subset of the results leading to... more Official gene symbols (HGNC) for our 20 NK signature genes and a subset of the results leading to their inclusion during curation, in particular bulk RNA-seq differential expression results and comparison to T cells for single-cell RNA-seq data from Tirosh et al (2016). For further details please refer to the Materials and Methods. LM22: CIBERSORT LM22 lists; LM7: Tosolini et al LM7 list.
Supplementary Figure 1 from The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by... more Supplementary Figure 1 from The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by Progastrin in Human Colorectal Cancer Cells
Supplementary Figure 4 from The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by... more Supplementary Figure 4 from The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by Progastrin in Human Colorectal Cancer Cells
Supplementary Figure Legends 1-4 from The Wnt Target Jagged-1 Mediates the Activation of Notch Si... more Supplementary Figure Legends 1-4 from The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by Progastrin in Human Colorectal Cancer Cells
Anz Journal of Surgery, Nov 1, 2022
Theranostics: a fifth pillar of contemporary cancer care? Cancer is a leading cause of mortality ... more Theranostics: a fifth pillar of contemporary cancer care? Cancer is a leading cause of mortality in Australia, with approximately 151 000 new diagnoses and 49 000 cancer-related deaths in 2021. 1 The oncological 'pillars' of surgery, chemotherapy and radiotherapy are being augmented by targeted molecular therapies and immunotherapy and the distinction between curative-intent and palliative-intent treatments has become blurred, as more and more patients live with cancer as a chronic condition, moving between treatment modalities as required. As the focus on personalized oncology intensifies, surgeons must understand each pillar of cancer care, and how they can be used as alternatives or adjuncts to surgery.
Annals of Oncology, Jun 1, 2018
Supplementary Figures S1-S6 from Phosphatidylethanol Accumulation Promotes Intestinal Hyperplasia... more Supplementary Figures S1-S6 from Phosphatidylethanol Accumulation Promotes Intestinal Hyperplasia by Inducing ZONAB-Mediated Cell Density Increase in Response to Chronic Ethanol Exposure
Chronic alcohol consumption is associated with increased risk of gastrointestinal cancer. High co... more Chronic alcohol consumption is associated with increased risk of gastrointestinal cancer. High concentrations of ethanol trigger mucosal hyperregeneration, disrupt cell adhesion, and increase the sensitivity to carcinogens. Most of these effects are thought to be mediated by acetaldehyde, a genotoxic metabolite produced from ethanol by alcohol dehydrogenases. Here, we studied the role of low ethanol concentrations, more likely to mimic those found in the intestine in vivo, and used intestinal cells lacking alcohol dehydrogenase to identify the acetaldehyde-independent biological effects of ethanol. Under these conditions, ethanol did not stimulate the proliferation of nonconfluent cells, but significantly increased maximal cell density. Incorporation of phosphatidylethanol, produced from ethanol by phospholipase D, was instrumental to this effect. Phosphatidylethanol accumulation induced claudin-1 endocytosis and disrupted the claudin-1/ZO-1 association. The resulting nuclear transl...
The protective role of Natural Killer (NK) cell tumour immunosurveillance has long been recognise... more The protective role of Natural Killer (NK) cell tumour immunosurveillance has long been recognised in colorectal cancer (CRC). However, as most patients show limited intra-tumoral NK cell infiltration, improving our ability to identify those with high NK cell activity might aid in dissecting the molecular features which could trigger strong response to NK cell-mediated immune killing. Here, a novel CRC-specific NK cell gene signature capable of inferring NK cell load in primary tissue samples was derived and validated in multiple patient CRC cohorts. The specificity of the signature is substantiated in tumour-infiltrating NK cells from primary CRC tumours at the single cell level, and the expression profile of each constituent gene is explored in NK cells of different maturation states, activation status and anatomical origin. Thus, in contrast with other NK cell gene signatures that have several overlapping genes across different immune cell types, our NK cell signature has been ex...
Frontiers in Immunology
The protective role of Natural Killer (NK) cell tumour immunosurveillance has long been recognise... more The protective role of Natural Killer (NK) cell tumour immunosurveillance has long been recognised in colorectal cancer (CRC). However, as most patients show limited intra-tumoral NK cell infiltration, improving our ability to identify those with high NK cell activity might aid in dissecting the molecular features which underlie NK cell sensitivity. Here, a novel CRC-specific NK cell gene signature that infers NK cell load in primary tissue samples was derived and validated in multiple patient CRC cohorts. In contrast with other NK cell gene signatures that have several overlapping genes across different immune cell types, our NK cell signature has been extensively refined to be specific for CRC-infiltrating NK cells. The specificity of the signature is substantiated in tumour-infiltrating NK cells from primary CRC tumours at the single cell level, and the signature includes genes representative of NK cells of different maturation states, activation status and anatomical origin. Our...
Cancers
The development of therapies that target specific disease subtypes has dramatically improved outc... more The development of therapies that target specific disease subtypes has dramatically improved outcomes for patients with breast cancer. However, survival gains have not been uniform across patients, even within a given molecular subtype. Large collections of publicly available drug screening data matched with transcriptomic measurements have facilitated the development of computational models that predict response to therapy. Here, we generated a series of predictive gene signatures to estimate the sensitivity of breast cancer samples to 90 drugs, comprising FDA-approved drugs or compounds in early development. To achieve this, we used a cell line-based drug screen with matched transcriptomic data to derive in silico models that we validated in large independent datasets obtained from cell lines and patient-derived xenograft (PDX) models. Robust computational signatures were obtained for 28 drugs and used to predict drug efficacy in a set of PDX models. We found that our signature fo...
Stem Cell Reports
Summary Tumor recurrence is often attributed to cancer stem cells (CSCs). We previously demonstra... more Summary Tumor recurrence is often attributed to cancer stem cells (CSCs). We previously demonstrated that down-regulation of Pregnane X Receptor (PXR) decreases the chemoresistance of CSCs and prevents colorectal cancer recurrence. Currently, no PXR inhibitor is usable in clinic. Here, we identify miR-148a as a targetable element upstream of PXR signaling in CSCs, which when over-expressed decreases PXR expression and impairs tumor relapse after chemotherapy in mouse tumor xenografts. We then develop a fluorescent reporter screen for miR-148a activators and identify the anti-helminthic drug niclosamide as an inducer of miR-148a expression. Consequently, niclosamide decreased PXR expression and CSC numbers in colorectal cancer patient-derived cell lines and synergized with chemotherapeutic agents to prevent CSC chemoresistance and tumor recurrence in vivo. Our study suggests that endogenous miRNA inducers is a viable strategy to down-regulate PXR and illuminates niclosamide as a neoadjuvant repurposing strategy to prevent tumor relapse in colon cancer.
Cancers, 2022
Geno- and phenotypic heterogeneity amongst cancer cell subpopulations are established drivers of ... more Geno- and phenotypic heterogeneity amongst cancer cell subpopulations are established drivers of treatment resistance and tumour recurrence. However, due to the technical difficulty associated with studying such intra-tumoural heterogeneity, this phenomenon is seldom interrogated in conventional cell culture models. Here, we employ a fluorescent lineage technique termed “optical barcoding” (OBC) to perform simultaneous longitudinal tracking of spatio-temporal fate in 64 patient-derived colorectal cancer subclones. To do so, patient-derived cancer cell lines and organoids were labelled with discrete combinations of reporter constructs, stably integrated into the genome and thus passed on from the founder cell to all its clonal descendants. This strategy enables the longitudinal monitoring of individual cell lineages based upon their unique optical barcodes. By designing a novel panel of six fluorescent proteins, the maximum theoretical subpopulation resolution of 64 discriminable sub...
Asia-pacific Journal of Clinical Oncology, 2018
Anaesthesia, 2021
SummaryPublished data suggest that the type of general anaesthesia used during surgical resection... more SummaryPublished data suggest that the type of general anaesthesia used during surgical resection for cancer may impact on patient long‐term outcome. However, robust prospective clinical evidence is essential to guide a change in clinical practice. We explored the feasibility of conducting a randomised controlled trial to investigate the impact of total intravenous anaesthesia with propofol vs. inhalational volatile anaesthesia on postoperative outcomes of patients undergoing major cancer surgery. We undertook a randomised, double‐blind feasibility and pilot study of propofol total intravenous anaesthesia or volatile‐based maintenance anaesthesia during cancer resection surgery at three tertiary hospitals in Australia and the USA. Patients were randomly allocated to receive propofol total intravenous anaesthesia or volatile‐based maintenance anaesthesia. Primary outcomes for this study were successful recruitment to the study and successful delivery of the assigned anaesthetic treat...
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Papers by Frédéric Hollande