Defeating cancer:the 150 most important questions in cancer research and clinical oncology

Despite all the human efforts and monetary investment over the last few decades,cancer is still a devastating threat to our life expectancy and quality of life in many parts of the world.The etiology of cancer varies.The genetic and epigenetic causes of cancer are heterogeneous and multifaceted.Early detection is still a

BICC1 drives pancreatic cancer progression by inducing VEGF-independent angiogenesis

VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors.Nevertheless,pancreatic adenocarcinoma(PAAD)cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways,thereby conferring resistance to VEGF inhibitors.Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD.The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth,and worse prognosis.In cells and mice with xenograft tumors,BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner.Mechanistically,as an RNA binding protein,BICC1 bounds to the 3’UTR of Lipocalin-2(LCN2)mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells.When its level is elevated,LCN2 binds to its receptor 24p3R,which directly phosphorylates JAK2 and activates JAK2/STAT3 signal,leading to increased production of an angiogenic factor CXCL1.Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice,and increased the tumor suppressive effect of gemcitabine.In conclusion,BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer,leading to resistance to VEGF inhibitors.BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.

WIP1 promotes cancer stem cell properties by inhibiting p38 MAPK in NSCLC

Cancer stem cells(CSCs)are a small population of stem cell-like cancer cells that can initiate tumors in vivo,and are the major source of cancer initiation,relapse,and drug resistance.We previously reported that the p38 MAPK,through its downstream effectors MK2 and HSP27,suppressed CSC properties by downregulating the expression of transcription factors that mediate stemness in non-small-cell lung cancer(NSCLC)cells,and that despite unaltered total expression of total p38 proteins,the levels of activated p38 were reduced in NSCLC tissues.However,the mechanism underlying the reduced levels of activated p38 in NSCLC is unknown.In this study,we identified WIP1,a p38 phosphatase frequently overexpressed in cancer,as a suppressor of p38 in a pathway that regulates CSC properties in NSCLC.Increased WIP1 expression correlated with reduced levels of activated p38,and with increased levels of a CSC marker in NSCLC tissues.Further investigation revealed that WIP1 promoted stemness-related protein expression and CSC properties by inhibiting p38 activity in NSCLC cells.WIP1 inhibitors are currently under development as anticancer drugs based on their ability to reactivate p53.We found that a WIP1 inhibitor suppressed stemness-related protein expression and CSC properties by activating p38 in NSCLC cells in vitro and in vivo.These studies have identified the WIP1–p38–MK2–HSP27 cascade as a novel signaling pathway that,when altered,promotes CSC properties in NSCLC development,and have defined novel mechanisms underlying the oncogenic activity of WIP1 and the anticancer efficacy of WIP1 inhibitors.

Role of extracellular vesicles secretion in paclitaxel resistance of prostate cancer cells

Aim:The development of chemotherapy resistance is the major obstacle in the treatment of advanced prostate cancer(PCa).Extracellular vesicles(EVs)secretion plays a significant role among different mechanisms contributing to chemoresistance.Hence,inhibition of EVs release may increase the efficacy of chemotherapeutic drugs against PCa.Methods:Paclitaxel(PTX)resistant PCa cells(PC3-R and DU145-R)were treated with GW4869,a known exosome biogenesis inhibitor.EVs were isolated from the conditioned media by ExoQuick-based precipitation method and characterized for concentration and size distribution by nanoparticle tracking analysis.The effect of GW4869 treatment on the survival and growth of PCa cells was assessed by MTT,and colony formation assays in vitro,and ectopic PC3-R xenografts in male athymic nude mice in vivo.The effect of other EV biogenesis inhibitors,imipramine and dimethyl amiloride(DMA),treatment was also analyzed on the survival of PC3-R cells.Results:GW4869(10-20μM)treatment of PTX resistant PCa cells significantly reduced the release of small EVs(50-100 nm size range)while increasing the release of larger EVs(>150 nm in size),and inhibited their clonogenicity.Moreover,GW4869(5-20μM)treatment(24-72h)significantly inhibited the survival of PC3-R cells in a dose-dependent manner.We observed a similar growth inhibition with both imipramine(5-20μg/mL)and DMA(5-20μg/mL)treatment in PC3-R cells.Furthermore,GW4869 treatment(IP)in mice bearing PC3-R xenografts significantly reduced the tumor weight(65%reduction,P=0.017)compared to the vehicle-treated control mice without causing any noticeable toxicity.Conclusion:Inhibiting the release of EVs could sensitize the resistant PCa cells to chemotherapy.

Precision medicine becomes reality- tumor type--agnostic therapy

Precision medicine just witnessed two breakthroughs in oncology in 2017.Pembrolizumab(Keytruda),Merck’s anti-programmed cell death-1(PD-1)monoclonal antibody(mAb),received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high(MSI-H)or deficient DNA mismatch repair(dMMR).Shortly after,nivolumab(Opdivo),Bristol-Myers Squibb’s anti-PD-1 mAb,gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy.These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated,and therefore established a precedent for tumor type-agnostic therapy.In the 2017 American Society for Clinical Oncology annual meeting,larotrectinib(LOXO-101),Loxooncology’s oral,potent,and selective inhibitor of tropomyosin receptor kinases(TRK),demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase(NTRK)-fusion proteins in adult and pediatric patients.Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features:(a)biomarker-based,well-defined rare patient population;(b)exceptionally high clinical efficacy,e.g.,near 40%overall response rate(ORR)for pem-brolizumab across 15 tumor types with MSI-H/dMMR and 75%ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins;(c)durable responses lasting at least 6 months with complete responses observed;and(d)parallel development in adult and pediatric populations.With increasing accessibility to genetic analysis tools such as next-generation sequencing,tumor type-agnostic therapy has become a reality,both during clinical development and in clinical practice.Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.

scLM:Automatic Detection of Consensus Gene Clusters Across Multiple Single-cell Datasets

In gene expression profiling studies,including single-cell RNA sequencing(scRNA-seq)analyses,the identification and characterization of co-expressed genes provides critical information on cell identity and function.Gene co-expression clustering in scRNA-seq data presents certain challenges.We show that commonly used methods for single-cell data are not capable of identifying co-expressed genes accurately,and produce results that substantially limit biological expectations of co-expressed genes.Herein,we present single-cell Latent-variable Model(scLM),a gene coclustering algorithm tailored to single-cell data that performs well at detecting gene clusters with significant biologic context.Importantly,scLM can simultaneously cluster multiple single-cell datasets,i.e.,consensus clustering,enabling users to leverage single-cell data from multiple sources for novel comparative analysis.scLM takes raw count data as input and preserves biological variation without being influenced by batch effects from multiple datasets.Results from both simulation data and experimental data demonstrate that scLM outperforms the existing methods with considerably improved accuracy.To illustrate the biological insights of scLM,we apply it to our in-house and public experimental scRNA-seq datasets.scLM identifies novel functional gene modules and refines cell states,which facilitates mechanism discovery and understanding of complex biosystems such as cancers.A user-friendly R package with all the key features of the scLM method is available at https://github.com/QSong-github/scLM.