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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

Classifying Bladder Cancer Subtypes

Urothelial carcinoma of the bladder is is estimated to have killed over 16,000 people in the United States in 2016. Like breast cancer, bladder cancer is a heterogeneous disease, and characterization of its various subtypes can be useful for forecasting prognosis and treatment efficacy. According to The Cancer Genome Atlas (TCGA) project, the mRNA expression profiles of bladder tumours can be used to cluster the tumors into four different categories: I - Papillary-like, II -Luminal A, III - basal/squamous-like, and IV - other (similar to III). However it is not clear whether these mRNA expression based clusters correlate with other molecular and genetic features of the tumor cells. In other words, do differences in mRNA expression profile contain the same information as differences in protein expression, micro RNA (miRNA) expression, copy number variation and somatic mutation data. We tried to recreate mRNA based bladder tumor clusters from other multi-omic data for 328 bladder cancer tumor samples using a special deep and wide belief network composed of restricted Boltzmann machines and a multilayer perceptron. For 10-fold cross validation, we got 79% average test accuracy which implies that that differences in mRNA expression between bladder tumor cells can be reliably, though not perfectly, inferred from different molecular and genetic features of the tumors.

cancer biology↗

bioRxiv2018

5-hydroxy-4′-nitro-7-propionyloxy-genistein inhibited invasion and metastasis via inactivating wnt/β-catenin signal pathway in human endometrial carcinoma JEC cells

Chemotherapy has been demonstrating more important roles in the treatment of carcinoma, but drug resistance and side effects restrict its usage in clinic, so developing new type of drug with low side effects and low-drug resistance has become a hot researching spot. The present study aimed to investigate the anticancer effects of 5-hydroxy-4-nitro-7-propionyloxy-genistein (HNPG) and elucidate its underlying molecular mechanism. The inhibitory effects of cell viability of HNPG were detected using MTT assay, flat plate clone formation method and Transwell assay. The distribution of cell cycle was analyzed using FCM method. The morphological alteration, root-mean-squared roughness (Rq), average roughness (Ra), Young's modulus and adhesive force were measured by AFM. qRT-PCR and western blotting analysis were used to explore the possible molecular mechanism. It was found that HNPG presented with dramatic activity against JEC cells in vitro, inhibited the proliferation and colony formation, attenuated invasion and migration ability, arrested cell cycle in G1 phase in dose-dependent manner. Simultaneously, cell body shrunk and pseudopod structure retracted, Rq and Ra reduced, Young's modulus and adhesive force increased, accompanied by {beta}-catenin, C-myc, Cyclin D1, MMP-2, MMP-7 and MMP-9 down-regulated. In summary, HNPG may be a novel candidate for chemotherapeutic drug.

cancer biology↗

bioRxiv2018

Single-Cell Transcriptome Analysis of Lineage Diversity and Microenvironment in High-Grade Glioma

BackgroundDespite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs). We sampled the cellular milieu of HGGs with massively-parallel single-cell RNA-Seq.\n\nResultsWhile HGG cells can resemble glia or even immature neurons and form branched lineage structures, mesenchymal transformation results in unstructured populations. Glioma cells in a subset of mesenchymal tumors lose their neural lineage identity, express inflammatory genes, and co-exist with marked myeloid infiltration, reminiscent of molecular interactions between glioma and immune cells established in animal models. Additionally, we discovered a tight coupling between lineage resemblance and proliferation among malignantly transformed cells. Glioma cells that resemble oligodendrocyte progenitors, which proliferate in the brain, are often found in the cell cycle. Conversely, glioma cells that resemble astrocytes, neuroblasts, and oligodendrocytes, which are non-proliferative in the brain, are generally non-cycling in tumors.\n\nConclusionsThese studies reveal a relationship between cellular identity and proliferation in HGG and distinct population structures that reflects the extent of neural and non-neural lineage resemblance among malignantly transformed cells.

cancer biology↗

bioRxiv2018

HDL-AuNPs-BMS nanoparticle conjugates as molecularly targeted therapy for leukemia

In previous work, gold nanoparticles (AuNPs) with adsorbed high-density lipoprotein (HDL) nanoparticles have been utilized to deliver oligonucleotides, yet HDL-AuNPs functionalized with small molecule inhibitors have not been systematically explored. Here, we report an AuNP-based therapeutic system (HDL-AuNPs-BMS) for acute myeloid leukemia (AML) by delivering BMS309403 (BMS), a small molecule that selectively inhibits AML-promoting factor fatty acid binding protein 4 (FABP4). HDL-AuNPs-BMS are synthesized using a gold nanoparticle as template to control conjugate size and ensure a spherical shape to engineer HDL-like nanoparticle containing BMS. The zeta potential and size of the HDL-AuNPs obtained from transmission electron microscopy (TEM) show that the nanoparticles are electrostatically stable and 25 nm in diameter. Functionally, compared to free drug, HDL-AuNPs-BMS conjugates are more readily internalized by AML cells and have more pronounced effect on downregulation of DNA methyltransferase 1 (DNMT1), reduction of global DNA methylation, and restoration of epigenetically-silenced tumor suppressor p15INK4b coupled with AML growth arrest. Importantly, systemic administration of HDL-AuNPs-BMS conjugates into AML-bearing mice inhibits DNMT1-dependent DNA methylation, induces AML cell differentiation and diminishes AML disease progression without obvious side effects. In summary, these data, for the first time, demonstrate HDL-AuNPs as an effective delivery platform with great potential to attach distinct inhibitors, and HDL-AuNPs-BMS conjugates as a promising therapeutic platform to treat leukemia.

cancer biology↗

bioRxiv2018

Cell-type specific expression of oncogenic and tumor suppressive microRNAs in the human prostate and prostate cancer

MiR-1 and miR-143 are frequently reduced in human prostate cancer (PCa), while miR-141 and miR-21 are frequently elevated. Consequently, these miRNAs have been studied as cell-autonomous tumor suppressors and oncogenes. However, the cell-type specificity of these miRNAs is not well defined in prostate tissue. Through two different microdissection techniques, and droplet digital RT-PCR, we quantified these miRNAs in the stroma and epithelium of radical prostatectomy specimens. In contrast to their purported roles as cell-autonomous tumor suppressors, we found miR-1 and miR-143 expression to be predominantly stromal. Conversely, miR-141 was predominantly epithelial. MiR-21 was detected in both stroma and epithelium. Strikingly, the levels of miR-1 and miR-143 were significantly reduced in tumor-associated stroma, but not tumor epithelium. Gene expression analyses in human cell lines, tissues, and prostate-derived stromal cultures support the cell-type selective expression of miR-1, miR-141, and miR-143. Analyses of the PCa Genome Atlas (TCGA-PRAD) showed a strong positive correlation between stromal markers and miR-1 and miR-143, and a strong negative correlation between stromal markers and miR-141. In these tumors, loss of miR-1 and gain of miR-21 was highly associated with biochemical recurrence. These data shed new light on stromal and epithelial miRNA expression in the PCa tumor microenvironment.

cancer biology↗

bioRxiv2018

phospho-ERK is a response biomarker to a combination of sorafenib and MEK inhibition in liver cancer

Treatment of liver cancer remains challenging, due to a paucity of drugs that target critical dependencies. Sorafenib is a multikinase inhibitor that is approved as the standard therapy for advanced hepatocellular carcinoma patients, but it can only provide limited survival benefit for patients. To investigate the cause of this limited therapeutic effect, we performed a CRISPR-Cas9 based synthetic lethality screen to search for kinases whose knockout synergize with sorafenib. We find that suppression of ERK2 sensitizes several liver cancer cell lines to sorafenib. Drugs inhibiting the MEK or ERK kinases reverse unresponsiveness to sorafenib in vitro and in vivo in a subset of liver cancer cell lines characterized by high levels of active phospho-ERK levels through synergistic inhibition of ERK kinase activity. Our data provide a combination strategy for treating liver cancer and suggest that tumors with activation of p-ERK, which is seen in some 30% of liver cancers, are most likely to benefit from such combinatorial treatment.

cancer biology↗

bioRxiv2018

MST1R/RON and EGFR in a complex with syndecans sustain carcinoma S-phase progression by preventing p38MAPK activation

Syndecan-4 (Sdc4) organizes a complex of receptors consisting of its homologue, Sdc2, the receptor tyrosine kinases EGFR and MST1R/RON, and the laminin-binding 3{beta}1 and 6{beta}4 integrins that depends on a docking site within its extracellular domain. A peptide mimetic of the extracellular docking site, synstatin-EGFR (SSTNEGFR), disrupts the receptor complex and prevents the invasion of non-transformed or carcinoma cells that relies on active EGFR. However, the peptide also prevents DNA replication that relies on active MST1R/RON and c-Abl kinase within the complex, resulting in rapid S-phase arrest of head & neck (HN) and breast carcinoma cells. SSTNEGFR does not affect DNA replication in non-transformed oral or breast epithelial cells, but it does block their EGF-dependent invasion. Although EGFR is required as a component of the complex, its kinase activity is not required to sustain S-phase progression in the carcinoma cells, perhaps explaining why many HN and breast carcinomas that overexpress EGFR are nonetheless refractory to EGFR inhibitors. The syndecan-organized receptor complex (Sdc:RTK:ITG complex) appears to suppress stress signals that would otherwise disrupt the replisome engaged in DNA synthesis. SSTNEGFR-treatment of carcinoma cells, or normal oral epithelial cells expressing stress-inducing HPV oncogenes, causes rapid activation of the p38 stress MAPK leading to loss of PCNA from the chromatin and cessation of DNA synthesis. This arrest is independent of the common DNA damage response (DDR) known to activate an S-phase checkpoint, revealing a novel arrest mechanism and a novel receptor complex that is activated on tumor cells to suppress stress-induced proliferation arrest.

cancer biology↗

bioRxiv2018

Beyond synthetic lethality: multiple gene interaction types play a key functional role in cancer

The phenotypic effect of perturbing a genes activity depends on the activity level of other genes, reflecting the notion that phenotypes are emergent properties of a network of functionally interacting genes. In the context of cancer, contemporary investigations have primarily focused on just one type of functional genetic interaction (GI) - synthetic lethality (SL). However, there may be additional types of GIs whose systematic identification would enrich the molecular and functional characterization of cancer. Here, we describe a novel data-driven approach called EnGIne, that applied to TCGA data identifies 71,946 GIs spanning 12 distinct types, only a small minority of which are SLs. The detected GIs explain cancer driver genes tissue-specificity and differences in patients response to drugs, and stratify breast cancer tumors into refined subtypes. These results expand the scope of cancer GIs and lay a conceptual and computational basis for future studies of additional types of GIs and their translational applications. The GI network is accessible online via a web portal [https://amagen.shinyapps.io/cancerapp/].

cancer biology↗

bioRxiv2018

Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R inhibitors

PurposeInsulin-like growth factor I (IGF1) signaling regulates breast cancer initiation and progression and associated cancer phenotypes. We previously identified E-cadherin (CDH1) as a repressor of IGF1 signaling and in this study examined how loss of E-cadherin affects IGF1R signaling and response to anti-IGF1R therapies in breast cancer.\n\nExperimental DesignBreast cancer cell lines were used to assess how altered E-cadherin levels regulate IGF1R signaling and response to two anti-IGF1R therapies. In situ proximity ligation assay (PLA) was used to define interaction between IGF1R and E-cadherin. TCGA RNA-seq and RPPA data was used to compare IGF1R activation in estrogen receptor positive (ER+) invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) tumors. ER+ ILC cell lines and xenograft tumor explant cultures were used to evaluate efficacy to IGF1R pathway inhibition in combination with endocrine therapy.\n\nResultsDiminished functional E-cadherin increased both activation of IGF1R signaling and efficacy to anti-IGF1R therapies. PLA demonstrated a direct endogenous interaction between IGF1R and E-cadherin at points of cell-cell contact. Increased expression of IGF1 ligand and levels of IGF1R phosphorylation were observed in E-cadherin deficient ER+ ILC compared to IDC tumors. IGF1R pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy and similarly IGF1R inhibition reduced proliferation in ILC tumor explant culture.\n\nConclusionsWe provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R targeted therapy, thus identifying the IGF1R pathway as a potential novel target in E-cadherin deficient breast cancers.\n\nSTATEMENT OF SIGNIFICANCEIGF1R signaling is an attractive therapeutic target in breast cancer due to its regulation of proliferation, migration, and invasion. However, clinical trials targeting IGF1R have largely been unsuccessful due to lack of biomarkers to stratify patients for therapeutic response. In this study, we demonstrate loss of E-cadherin as a potential biomarker for response to anti-IGF1R therapy, and show efficacy of IGF1R inhibition in ER+ ILC in combination with endocrine therapy. Patients with ER+ ILC have poorer long-term outcomes than patients with ER+ IDC and have a propensity for increased late recurrences, highlighting the need for improved therapeutic strategies for this subtype of breast cancer. Here, we credential IGF1R inhibition as a novel therapeutic strategy in combination with endocrine therapy for the treatment of ER+ ILC.

cancer biology↗

bioRxiv2018

Role of IQGAP1 in Head and Neck Carcinogenesis

Head and neck squamous cell carcinoma (HNSCC) is a common cancer in humans. Phosphoinositide 3-kinase (PI3K)/AKT signaling, along with its downstream effector mTOR, is one of the most frequently altered pathways in HNSCC, and is downstream of growth factor signaling including that mediated by epidermal growth factor receptor (EGFR), which is also commonly upregulated in HNSCC. Recently, IQ motif-containing GTPase activation protein 1 (IQGAP1) has been reported to function as a scaffold for the enzymes involved in the PI3K/AKT signaling pathway. Iqgap1 gene expression is increased in human HNSCCs, raising the hypothesis that it acts as an oncogene in this cancer. Whether IQGAP1 is necessary for HNSCC development as well as what is its underlying mechanism are both unknown. Here we report on the role of IQGAP1 in HNSCC by performing a combination of in vitro studies using human cancer cell lines, and in vivo studies using a well-validated preclinical mouse model for HNSCC that is known to depend upon EGFR signaling. Cells knocked out for IQGAP1 lost AKT signaling. Disruption of IQGAP1-scaffolded PI3K/AKT signaling using a peptide that interferes with the ability of IQGAP1 to bind to PI3K reduced HNSCC cell survival. In vivo studies utilizing Iqgap1-null (Iqgap1-/-) mice demonstrated that IQGAP1 is necessary for efficient PI3K signaling upon EGF-stimulation. Treatment of Iqgap1-/- mice with the oral carcinogen, 4-nitroquinoline 1-oxide (4NQO), Iqgap1-/- led to significantly lower multiplicities of cancer foci as well as significantly lower numbers of high grade cancers than observed in similarly treated Iqgap1+/+ mice. IQGAP1 protein was increased in its expression in HNSCCs arising in the Iqgap1+/+ mice, consistent with that seen in human HNSCCs. We also observed a significant down-regulation of PI3K signaling in 4NQO-induced HNSCCs arising in the Iqgap1-/- mice, consistent with IQGAP1 contributing to carcinogenesis by promoting PI3K signaling. Our studies, therefore, support the hypothesis that IQGAP1 acts as an oncogene in head and neck carcinogenesis, and provide mechanistic insight into its role.

cancer biology↗

bioRxiv2018

Building a tumor atlas: integrating single-cell RNA-Seq data with spatial transcriptomics in pancreatic ductal adenocarcinoma

To understand tissue architecture it is necessary to understand both which cell types are present and their physical relationships to one another. Single-cell RNA-Seq (scRNA-Seq) has made significant progress towards the unbiased and systematic characterization of cell populations within a tissue by studying hundreds and thousands of cells in a single experiment. However, the characterization of the spatial organization of individual cells within a tissue has been more elusive. The recently introduced spatial transcriptomics method (ST) reveals the spatial pattern of gene expression within a tissue section at a resolution of a thousand 100 m spots across the tissue, each capturing the transcriptomes of [~]10-20 cells. Here, we present an approach for the integration of scRNA-Seq and ST data generated from the same sample of pancreatic cancer tissue. Using markers for cell types identified by scRNA-Seq, we robustly deconvolved the cell type composition of each ST spot to generate a spatial atlas of cell proportions across the tissue. Studying this atlas, we found that distinct spatial localizations accompany each of the cell populations that we identified. Our results provide a framework for creating a tumor atlas by mapping single-cell populations to their spatial region, as well as the inference of cell architecture in any tissue.

cancer biology↗

bioRxiv2018

Truncation and Motif Based Pan-Cancer Analysis Highlights Novel Tumor Suppressing Kinases.

A major challenge in cancer genomics is identifying driver mutations from the large number of neutral passenger mutations within a given tumor. Here, we utilize motifs critical for kinase activity to functionally filter genomic data to identify driver mutations that would otherwise be lost within mutational noise. In the first step of our screen, we define a putative tumor suppressing kinome by identifying kinases with truncation mutations occurring within or before the kinase domain. We aligned these kinase sequences and, utilizing data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas databases, identified amino acids that represent predicted hotspots for loss-of-function mutations. The functional consequences of new LOF mutations were validated and the top 15 hotspot LOF residues were used in a pan-cancer analysis to define the tumor-suppressing kinome. A ranked list revealed MAP2K7 as a candidate tumor suppressor in gastric cancer, despite the mutational frequency of MAP2K7 falling within the mutational noise for this cancer type. The majority of mutations in MAP2K7 abolished catalytic activity compared to the wild type kinase, consistent with a tumor suppressive role for MAP2K7 in gastric cancer. Furthermore, reactivation of the JNK pathway in gastric cancer cells harboring LOF mutations in MAP2K7 or JNK1 suppresses clonogenicity and growth in soft agar, demonstrating the functional importance of inactivating the JNK pathway in gastric cancer. In summary, our data highlights a broadly applicable strategy to identify functional cancer driver mutations leading us to define the JNK pathway as tumor suppressive in gastric cancer.\n\nSummaryA unique computational pan-cancer analysis pinpoints novel tumor suppressing kinases, and highlights the power of functional genomics by defining the JNK pathway as tumor suppressive in gastric cancer.

cancer biology↗

bioRxiv2018

Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration ofinflammatory immune cells in EGFR mutant lung tumors

Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells. Using mouse models, we studied the immunological profile of mutant EGFR-driven lung tumors before and after erlotinib treatment. We found that erlotinib triggered the recruitment of inflammatory T cells into the lungs. Interestingly, this phenotype could be recapitulated by tumor regression mediated by deprivation of the EGFR oncogene indicating that tumor regression alone was sufficient for these immunostimulatory effects. Erlotinib treatment also led to increased maturation of myeloid cells and an increase in CD40+ dendritic cells. Our findings lay the foundation for understanding the effects of TKIs on the tumor microenvironment and highlights potential avenues for investigation of targeted and immuno-therapy combination strategies to treat EGFR mutant lung cancer.

cancer biology↗

bioRxiv2018

Targeting the SUMO pathway primes all-trans-retinoic acid-induced differentiation of non promyelocytic Acute Myeloid Leukemias

Differentiation therapies using All-trans-retinoic acid (ATRA) are highly efficient at treating Acute Promyelocytic Leukemia (APL), a minor subtype of Acute Myeloid Leukemias (AML). However, their efficacy, if any, is very limited in the case of non-APL AMLs. We report here that the inhibition of SUMOylation, a post-translational modification related to ubiquitinylation, restores the pro-differentiation and anti-proliferative activities of retinoids in non-APL AMLs. Controlled inhibition of SUMOylation with pharmacological inhibitors (2-D08 or anacardic acid), or via overexpression of SENP desumoylases, strongly enhances the ATRA-induced expression of key genes involved in differentiation, proliferation and apoptosis in non-APL AML cells. This activates ATRA-induced terminal myeloid differentiation and reduces cell proliferation and viability, including in AML cells resistant to chemotherapeutic drugs. Conversely, enhancement of SUMOylation by overexpressing the SUMO-conjugating enzyme Ubc9 dampens the expression of ATRA-responsive genes and prevents differentiation. Thus, inhibition of the SUMO pathway is a promising strategy to sensitize non-APL AML patients to retinoids and improve the treatment of this poor prognosis cancer, which has not significantly changed over the past 40 years.

cancer biology↗

bioRxiv2018

Parp3 promotes long-range end-joining in murine cells

Chromosomal rearrangements, including translocations, are early and essential events in the formation of many tumors. Previous studies that defined the genetic requirements for rearrangement formation have identified differences between murine and human cells, most notably in the role of classical- and alternative-nonhomologous end joining factors (NHEJ). We reported that poly(ADP)ribose polymerase 3 (PARP3) promotes chromosomal rearrangements induced by endonucleases in multiple human cell types. In contrast to c-NHEJ factors, we show here that Parp3 also promotes rearrangements in murine cells, including translocations in murine embryonic stem cells (mESCs), class switch recombination in primary B cells and inversions in tail fibroblasts that generate Eml4-Alk fusions. In mESCs, Parp3-deficient cells had shorter deletion lengths at translocation junctions. This was corroborated using next-generation sequencing of Eml4-Alk junctions in tail fibroblasts and is consistent with a role for Parp3 in promoting the processing of DNA double-strand breaks. We confirmed a previous report that Parp1 also promotes rearrangement formation. In contrast with Parp3, rearrangement junctions in the absence of Parp1 had longer deletion lengths, suggesting Parp1 may suppress DSB processing. Together, these data indicate that Parp3 and Parp1 promote rearrangements with distinct phenotypes.

cancer biology↗

bioRxiv2018

Genome-wide identification of CDC34 that stabilizes EGFR and promotes lung carcinogenesis

To systematically identify ubiquitin pathway genes that are critical to lung carcinogenesis, we used a genome-wide silencing method in this study to knockdown 696 genes in non-small cell lung cancer (NSCLC) cells. We identified 31 candidates that were required for cell proliferation in two NSCLC lines, among which the E2 ubiquitin conjugase CDC34 represented the most significant one. CDC34 was elevated in tumor tissues in 67 of 102 (65.7%) NSCLCs, and smokers had higher CDC34 than nonsmokers. The expression of CDC34 was inversely associated with overall survival of the patients. Forced expression of CDC34 promoted, whereas knockdown of CDC34 inhibited lung cancer in vitro and in vivo. CDC34 bound EGFR and competed with E3 ligase c-Cbl to inhibit the polyubiquitination and subsequent degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del(exon 19)-driven lung cancer in mice, knockdown of CDC34 by lentivirus mediated transfection of short hairpin RNA significantly inhibited tumor formation. These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to inhibit ubiquitination and subsequent degradation of oncoprotein substrate, and CDC34 represents an attractive therapeutic target for NSCLCs with or without drug-resistant EGFR mutations.

cancer biology↗

bioRxiv2018

RNAi screening of the tyrosine kinome in primary patient samples of acute myeloid leukemia

Targeted therapy has proven to be successful in improving outcomes across multiple cancer types. However, many challenges still remain for implementation of this strategy in most patient cohorts, especially with the challenges of identifying the specific mutations or abnormalities in a heterogeneous tumor that are functionally significant. Previously, we developed a functional screening assay, RNAi-assisted protein target identification (RAPID) technology, which evaluates the viability of tumor cells after exposure to siRNAs against members of the tyrosine kinome and NRAS/KRAS. Here, we publish the comprehensive results of this screen for 332 primary AML patient samples. Data from these screening efforts have already helped identify previously unknown therapeutic targets, and will continue to provide insights into better treatment strategies for these patients.

cancer biology↗

bioRxiv2018

CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance

Metastasis is the primary cause of cancer patient morbidity and mortality but due to persisting gaps in our knowledge, it remains untreatable. Metastases often occur as patients' tumors progress or recur after initial therapy. Tumor recurrence at the primary site may be driven by a cancer stem-like cell or tumor progenitor cell, while recurrence at a secondary site is driven by metastatic cancer stem cells or metastasis-initiating cells. Ongoing efforts are aimed at identifying and characterizing these stem-like cells driving recurrence and metastasis. One potential marker for the cancer stem-like cell subpopulation is CD117/c-kit, a tyrosine kinase receptor associated with cancer progression and normal stem cell maintenance. In our analyses, CD117 was expressed in several tissues and was highly expressed in bone marrow progenitor cells. Also, we uncovered that CD117 gene amplifications and mutations occurred in multiple cancers. Further, activation of CD117 by its ligand stem cell factor (SCF; kit ligand) in the progenitor cell niche stimulates several signaling pathways driving proliferation, survival, and migration. These signaling pathways were commonly altered in patients with CD117 amplifications and mutations. Here, we examine evidence that the SCF/CD117 signaling axis controls cancer progression through the regulation of stemness and resistance to tyrosine kinase inhibitors.\n\nAbbreviations

cancer biology↗