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Results for “Cancer Biology”

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bioRxiv2019

HDAC and MAPK/ERK Inhibitors Cooperate to Reduce Viability and Stemness Phenotype in Medulloblastoma

Medulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precursors in the developing cerebellum, is the most common malignant brain tumor of childhood. Recurrent and metastatic disease is the principal cause of death and may be related to resistance within cancer stem cells (CSCs). Chromatin state is involved in maintaining signaling pathways related to stemness, and inhibition of histone deacetylase enzymes (HDAC) has emerged as an experimental therapeutic strategy to target this cell population. Here, we observed antitumor actions and changes in stemness induced by HDAC inhibition in MB. Analyses of tumor samples from patients with MB showed that the stemness markers BMI1 and CD133 are expressed in all molecular subgroups of MB. The HDAC inhibitor (HDACi) NaB reduced cell viability and expression of BMI1 and CD133 and increased acetylation in human MB cells. Enrichment analysis of genes associated with CD133 or BMI1 expression showed mitogen-activated protein kinase (MAPK)/ERK signaling as the most enriched processes in MB tumors. MAPK/ERK inhibition reduced expression of the stemness markers, hindered MB neurosphere formation, and its antiproliferative effect was enhanced by combination with NaB. These results suggest that combining HDAC and MAPK/ERK inhibitors may be a novel and more effective approach in reducing MB proliferation when compared to single-drug treatments, through modulation of the stemness phenotype of MB cells.

cancer biology↗

bioRxiv2019

Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas

The use of mathematical models for personalization of cancer therapies and raising hypothesis of potential clinical impact is an emerging topic in the interface between mathematics and oncology. Here we put forward a mathematical model describing the response of low-grade (WHO grade II) oligodendrogliomas (LGO) to temozolomide (TMZ). The model described the longitudinal volumetric dynamics of tumor response to TMZ of a cohort of 11 LGO patients treated with TMZ. After finding patient-specific parameters, different therapeutical strategies were tried computationally on the in-silico twins of those patients. Chemotherapy schedules with larger-than-standard rest periods between consecutive cycles had either the same or better long-term efficacy than the standard 28-day cycles. The results were confirmed in a large virtual clinical trial including 2000 patients. These long-cycle schemes would also have reduced toxicity and defer the appearance of resistances.\n\nOn the basis of those results, a combination scheme consisting of five induction TMZ cycles given monthly plus 12 maintenance cycles given every three months was found to provide substantial survival benefits for the in-silico twins of the 11 LGO patients (median 5.69 years, range: 0.67 to 68.45 years) and in a large virtual trial including 2000 patients. This scheme could be useful for defining a standardized TMZ treatment for LGO patients with survival benefits.\n\nAuthor summaryA mathematical model described the longitudinal volumetric growth data of grade II oligodendrogliomas patients and their response to temozolomide. The model was used to explore alternative therapeutical protocols for the in-silico twins of the patients and in virtual clinical trials. The simulations show that enlarging the time interval between chemotherapy cycles would maintain the therapeutical efficacy, while limiting toxicity and defering the development of resistances. This may allow for improved drug-exposure by administering a larger number of cycles for longer treatment periods. A scheme based on this idea consisting of an induction phase (5 consecutive cycles, 1 per month) and a maintenance phase (12 cycles given in three-months intervals) led to substantial survival benefits in-silico.

cancer biology↗

bioRxiv2019

PIK3CA in KrasG12D/Trp53R172H Tumor Cells Promotes Immune Evasion by Limiting Infiltration of T Cells in a Model of Pancreatic Cancer

The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapies. Here we show using a syngeneic orthotopic implantation model of pancreatic cancer that Pik3ca regulates tumor immunogenicity. Genetic silencing of Pik3ca in KrasG12D/Trp53R172H-driven pancreatic tumors leads to infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast, Pik3ca-null tumors implanted in T cell-deficient mice progress and kill all of the animals. Adoptive transfer of tumor antigen-experienced T cells eliminates Pik3ca-null tumors in immunodeficient mice. Loss of PIK3CA or inhibition of its effector, AKT, increases the expression of MHC Class I and CD80 on tumor cells. These changes contribute to the increased susceptibility of Pik3ca-null tumors to T cell surveillance. These results indicate that tumor cell PIK3CA-AKT signaling limits T cell recognition and clearance of pancreatic cancer cells. Strategies that target this pathway may yield an effective immunotherapy for this cancer.\n\nSIGNIFICANCEPIK3CA-AKT signaling in pancreatic cancer cells limits T cell infiltration and clearance of tumors by suppressing the surface expression of MHC Class I and CD80. Targeting the PIK3CA-AKT pathway in tumor cells provides a new avenue for discovery of novel pancreatic cancer immunotherapies.

cancer biology↗

bioRxiv2019

C-terminal HSP90 Inhibitors Block the HSP90:HIF-1a Interaction and Inhibit the Cellular Hypoxic Response

Hypoxia Inducible Factor (HIF) is a transcription factor activated by low oxygen, which is common in solid tumours. HIF controls the expression of genes involved in angiogenesis, chemotherapy resistance and metastasis. The chaperone HSP90 (Heat Shock Protein 90) stabilizes the subunit HIF-1 and prevents degradation. Previously identified HSP90 inhibitors bind to the N-terminal pocket of HSP90 which blocks binding to HIF-1, and produces HIF-1 degradation. N-terminal inhibitors have failed in the clinic as single therapy treatments due in part because they induce a heat shock response, which increases chemotherapy resistance. SM molecules are HSP90 inhibitors that bind to the C-terminus and do not activate the heat shock response. The effects of C-terminal HSP90 inhibitors on HIF-1 are unreported. Herein we show that SM compounds block binding between HSP90 and HIF-1, leading to HIF-1 degradation through the proteasome using the PHD/pVHL pathway in hypoxic conditions. The SM compounds decrease HIF-1 target gene expression at the mRNA and protein level under hypoxia in colorectal cancer cells, leading to cell death, without inducing a heat shock response. Our results suggest that targeting the C-terminus of HSP90 blocks the hypoxic response and may be an effective anti-cancer strategy.

cancer biology↗

bioRxiv2019

Parallel signaling through IRE1α and PERK regulates pancreatic neuroendocrine tumor growth and survival

Master regulators of the unfolded protein response (UPR)--IRE1 and PERK-- promote adaptation or apoptosis depending on levels of endoplasmic reticulum (ER) stress. While the UPR is activated in many cancers, its effects on tumor growth remain unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNETs) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. For the nearly 1,500 Americans diagnosed with PanNETs annually, surgery is the only potentially curative treatment; however the five-year survival is extremely low for those who develop metastatic disease. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. We then used genetic and pharmacologic approaches to modulate IRE1 and PERK in cultured cells and xenograft and spontaneous genetic (RIP-Tag2) mouse models of PanNETs. We found that UPR signaling is optimized for adaptation and that inhibiting either IRE1 or PERK leads to hyperactivation and apoptotic signaling through the reciprocal arm, thereby halting tumor growth and survival. Our results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers experiencing elevated ER stress.\n\nSignificanceThe unfolded protein response (UPR) is upregulated in human pancreatic neuroendocrine tumors and its genetic or pharmacological inhibition significantly reduces tumor growth in preclinical models, providing strong rationale for targeting the UPR in neoplasms with elevated ER stress.

cancer biology↗

bioRxiv2019

SAMHD1 regulates human papillomavirus 16 induced cell proliferation and viral replication during differentiation of oral keratinocytes.

Human papillomaviruses induce a host of anogenital cancers, and also oropharyngeal cancer (HPV+OPC); HPV16 is causative in around 90% of HPV+OPC. Using TERT immortalized \"normal\" oral keratinocytes (NOKs) we have identified significant host gene reprogramming by HPV16 (NOKs+HPV16), and demonstrated that NOKs+HPV16 support late stages of the viral life cycle. Expression of the cellular dNTPase and homologous recombination factor SAMHD1 is transcriptionally regulated by HPV16 in NOKs, and here we demonstrate that E6 and E7 regulate expression of SAMHD1 at the transcriptional and post-transcriptional levels. CRISPR/Cas9 removal of SAMHD1 from NOKs and NOKs+HPV16 demonstrate that SAMHD1 controls cell proliferation of NOKs only in the presence of HPV16; deletion of SAMHD1 promotes hyper-proliferation of NOKs+HPV16 cells in organotypic raft cultures but has no effect on NOKs. Viral replication is also elevated in the absence of SAMHD1. This new system has allowed us to identify a specific interaction between SAMHD1 and HPV16 that regulates host cell proliferation and viral replication; such studies are problematic in non-immortalized primary oral keratinocytes due to their limited lifespan. To confirm the relevance of our results we repeated the analysis with human tonsil keratinocytes immortalized by HPV16 (HTK16) and observe the same hyper-proliferative phenotype following CRISPR/Cas9 editing of SAMHD1. Identical results were obtained with three independent CRISPR/Cas9 guide RNAs. The isogenic pairing of NOKs with NOKs+HPV16, combined with HTK16, presents a unique system to identify host genes whose products functionally interact with HPV16 to regulate host cellular growth in oral keratinocytes.\n\nImportanceHead and neck cancer is the sixth most common cancer worldwide. The incidence of HPV+OPC has been rising steadily since the 1970s and has recently reached epidemic proportions, according to the WHO. Upwards of 70% of the 600,000 new OPC cases per year are HPV positive, with high-risk type 16 present in 90% of those incidences. A better understanding of the viral life cycle will facilitate the development of novel therapeutics to combat this ongoing epidemic, as well as other HPV positive cancers. Here we present a unique oral keratinocyte model to identify host proteins that specifically interact with HPV16. Using this system, we report that a cellular gene, SAMHD1, is regulated by HPV16 at the RNA and protein level in oral keratinocytes. Elimination of SAMHD1 from these cells using CRISPR/Cas9 editing promotes enhanced cellular proliferation by HPV16 in oral keratinocytes and elevated viral replication, but not in keratinocytes that do not have HPV16. Our study demonstrates a specific intricate interplay between HPV16 and SAMHD1 during the viral life cycle and establishes a unique model system to assist exploring host factors critical for HPV pathogenesis.

cancer biology↗

bioRxiv2019

Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma; 40% of patients relapse following a complete response or are refractory to therapy. The activated subtype of diffuse large B-cell lymphoma relies upon B-cell receptor signaling for survival; this signaling can be modulated by the activity of Brutons tyrosine kinase. Targeting that kinase with its inhibitor ibrutinib provides a potential therapeutic approach for the activated B-cell subtype of diffuse large B-cell lymphoma. However, non-Hodgkin lymphoma is often resistant to ibrutinib or soon develops resistance after exposure to it. In this study, we explored the development of acquired ibrutinib resistance. After generating three isogenic ibrutinib-resistant diffuse large B-cell lymphoma cell lines, we investigated the deregulated pathways that are associated with colony formation, growth rates, and tumorigenic properties. We found that reduced levels of Brutons tyrosine kinase and enhanced phosphatidylinositol 3-kinase/AKT signaling were hallmarks of these ibrutinib-resistant cells. Upregulation of phosphatidylinositol-3-kinase-beta expression in those cells drove resistance and was reversed by the blocking activity of phosphatidylinositol-3-kinase-beta/delta. Treatment with the selective phosphatidylinositol-3-kinase-beta/delta dual inhibitor KA2237 reduced both tumorigenic properties and survival-based phosphatidylinositol-3-kinase/AKT/mTOR signaling of these ibrutinib-resistant cells. Additionally, combining KA2237 with currently available chemotherapeutic agents synergistically inhibited the metabolic growth of these ibrutinib-resistant cells. This study elucidates the compensatory upregulated phosphatidylinositol-3-kinase/AKT axis that emerges in ibrutinib-resistant cells.

cancer biology↗

bioRxiv2019

Development of Human Neuroblastomas in Mouse-Human Neural Crest Chimeras

Neuroblastoma (NB), derived from the neural crest (NC), is the most common pediatric extracranial solid tumor. Here we establish a platform that allows studying human NBs in mouse-human NC chimeras. Chimeric mice were produced by injecting human NC cells carrying NB relevant oncogenes in-utero into gastrulating mouse embryos. The mice developed tumors composed of a heterogenous cell population that closely resembled that seen in primary NBs of patients but were significantly different from homogenous tumors formed in xenotransplantation models. The human tumors emerged in immunocompetent hosts and were extensively infiltrated by mouse cytotoxic T cells reflecting a vigorous host anti-tumor immune response. However, the tumors blunted the immune response by inducing infiltration of regulatory T cells and expression of immune checkpoints similar to escape mechanisms seen in human cancer patients. Thus, this experimental platform allows studying human tumor initiation, progression, manifestation and tumor - immune-system interactions in an animal model system.

cancer biology↗

bioRxiv2019

Acute Myeloid Leukemia Driven by the CALM-AF10 Fusion Gene is Dependent on BMI1

A subset of acute myeloid and lymphoid leukemia cases harbor a t(10;11)(p13;q14) translocation resulting in the CALM-AF10 fusion gene. Standard chemotherapeutic strategies are often ineffective in treating patients with CALM-AF10 fusions. Hence, there is an urgent need to identify molecular pathways dysregulated in CALM-AF10-positive leukemias which may lay the foundation for novel targeted therapies. Here we demonstrate that the Polycomb Repressive Complex 1 gene BMI1 is consistently overexpressed in adult and pediatric CALM-AF10-positive leukemias. We demonstrate that genetic Bmi1 depletion abrogates CALM-AF10-mediated transformation of murine hematopoietic stem and progenitor cells (HSPCs). Furthermore, CALM-AF10-positive murine and human AML cells are profoundly sensitive to the small-molecule BMI1 inhibitor PTC209 as well as to PTC596, a compound in clinical development that has been shown to result in downstream degradation of BMI1 protein. PTC-596 significantly prolongs survival of mice injected with a human CALM-AF10 cell line in a xenograft assay. In summary, these results validate BMI1 as a bonafide candidate for therapeutic targeting in AML with CALM-AF10 rearrangements.

cancer biology↗

bioRxiv2019

Direct conversion of human fibroblasts to liver cancer cells

Cancer is the most complex genetic disease known, with mutations implicated in more than 250 genes. However, it is still elusive which specific mutations found in human patients lead to tumorigenesis. Here we show that a combination of oncogenes that is characteristic of liver cancer (CTNNB1, TERT, MYC) induces senescence in human fibroblasts and primary hepatocytes. However, reprogramming fibroblasts to a liver progenitor fate, induced hepatocytes (iHeps), makes them sensitive to transformation by the same oncogenes. The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. These results show that tumorigenesis is triggered by a combination of three elements: the set of driver mutations, the cellular lineage, and the state of differentiation of the cells along the lineage. Our results provide direct support for the role of cell identity as a key determinant in transformation, and establish a paradigm for studying the dynamic role of oncogenic drivers in human tumorigenesis.

cancer biology↗

bioRxiv2019

Simplified Molecular Classification of Lung Adenocarcinomas Based on EGFR, KRAS, and TP53 Mutations

IntroductionGene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications. To facilitate stratification of patients with this disease into similar molecular subtypes, we developed and validated a simple, mutually exclusive classification.\n\nMethodsMutational status of EGFR, KRAS, and TP53 was used to define six mutually exclusive molecular subtypes. A development cohort of 283 cytology specimens of lung adenocarcinoma was used to evaluate the associations between the proposed classification and clinicopathologic variables including demographic characteristics, smoking history, fluorescence in situ hybridization and molecular results. For validation and prognostic assessment, 63 of the 283 cytology specimens with available survival data were combined with a separate cohort of 428 surgical pathology specimens of lung adenocarcinoma.\n\nResultsThe proposed classification yielded significant associations between these molecular subtypes and clinical and prognostic features. We found better overall survival in patients who underwent surgery and had tumors enriched for EGFR mutations. Worse overall survival was associated with older age, stage IV disease, and tumors with comutations in KRAS and TP53. Interestingly, neither chemotherapy nor radiation therapy showed benefit to overall survival.\n\nConclusionsThe mutational status of EGFR, KRAS, and TP53 can be used to easily classify lung adenocarcinoma patients into six subtypes that show a relationship with prognosis, especially in patients who underwent surgery, and these subtypes are similar to classifications based on more complex genomic methods reported previously.

cancer biology↗

bioRxiv2019

Aberrations in Notch-Hedgehog signalling reveal cancer stem cells harbouring conserved oncogenic properties associated with hypoxia and immunoevasion

Background: Cancer stem cells (CSCs) have innate abilities to resist even the harshest of therapies. To eradicate CSCs, parallels can be drawn from signalling modules that orchestrate pluripotency. Notch-Hedgehog hyperactivation are seen in CSCs, yet, not much is known about their conserved roles in tumour progression across cancers. Methods: Employing a comparative approach involving 21 cancers, we uncovered clinically-relevant, pan-cancer drivers of Notch and Hedgehog. GISTIC datasets were used to evaluate copy number alterations. Receiver operating characteristic and Cox regression were employed for survival analyses. Results: We identified a Notch-Hedgehog signature of 13 genes exhibiting high frequencies of somatic amplifications leading to transcript overexpression. The signature successfully predicted patients at risk of death in five cancers(n=2,278): glioma(P<0.0001), clear cell renal cell(P=0.0022), papillary renal cell(P=0.00099), liver(P=0.014) and stomach(P=0.011). The signature was independent of other clinicopathological parameters and offered additional resolution to stratify similarly-staged tumours. High-risk patients exhibited features of stemness and had more hypoxic tumours, suggesting that hypoxia may influence CSC behaviour. Notch-Hedgehog+ CSCs had an immune privileged phenotype associated with increased regulatory T cell function. Conclusion: This study will set the stage for exploring adjuvant therapy targeting the Notch-Hedgehog axis to help optimise therapeutic regimes leading to successful CSC elimination.

cancer biology↗

bioRxiv2019

Comprehensive identification of survival-associated genes for cancers

Prognostic signature is important in estimating cancer risk, subtyping cancer, and planning treatment. A single gene as a prognostic marker would facilitate the development of a clinical test. Here we showed that the number of prognostic and diagnostic genes differ greatly across cancers. By considering both the survival difference and the fold change of expression in cancer, we revealed the prognostic genes for each cancer and found twenty two genes with both diagnostic and prognostic capacity. The universal prognostic genes (CDC20, CDCA8, ASPM, ERCC6L, and GTSE1) mainly function in the spindle assembly checkpoint, and show more statistical links to mutated pathways, suggesting that expression of these genes can be altered by mutations from many pathways. Briefly, we systematically identified the prognostic genes and revealed the associations between the prognostic genes and genes mutated in cancer. Keywords: Prognostic gene; Cancer; Mutation; Diagnosis

cancer biology↗

bioRxiv2019

Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models

The development of immune checkpoint inhibitors represents a major breakthrough in cancer therapy. Nevertheless, a substantial number of patients fail to respond to checkpoint pathway blockade. {beta}-catenin is the key transcriptional regulator of WNT/{beta}-catenin signaling. Evidence for {beta}-catenin-mediated immune evasion is found in 13% of all cancers, 42% of primary cutaneous melanoma and a mouse melanoma model. Currently, there are no therapeutic strategies available for targeting WNT/{beta}-catenin signaling to counteract checkpoint inhibitor resistance in melanoma. Here we report that a specific small-molecule tankyrase inhibitor, G007-LK, attenuates WNT/{beta}-catenin and YAP signaling pathways in the syngeneic murine B16-F10 melanoma model enabling sensitivity to anti-PD-1 immune checkpoint therapy. RNA sequencing of 18 tankyrase inhibitor-treated human melanoma cell lines and B16-F10 cells revealed a transcriptional response profile for a subpopulation. This cell line sub-group displayed elevated baseline YAP signaling activity and was susceptible to reduce melanocyte inducing transcription factor (MITF) expression upon tankyrase inhibition.

cancer biology↗

bioRxiv2019

Oncogenic Notch promotes long-range regulatory interactions within hyperconnected 3D cliques

Chromatin loops enable transcription factor-bound distal enhancers to interact with their target promoters to regulate transcriptional programs. Although developmental transcription factors, such as active forms of Notch, can directly stimulate transcription by activating enhancers, the effect of their oncogenic subversion on the 3-dimensional (3D) organization of the cancer genome is largely undetermined. By mapping chromatin looping genome-wide in Notch-dependent triple-negative breast cancer and B-cell lymphoma, we show that far beyond the well-characterized role of Notch as an activator of distal enhancers, Notch regulates its direct target genes through establishing new long-range regulatory interactions. Moreover, a large fraction of Notch-promoted regulatory loops forms highly interacting enhancer and promoter spatial clusters, termed "3D cliques". Loss-and gain-of-function experiments show that Notch preferentially targets hyperconnected 3D cliques that regulate the expression of crucial proto-oncogenes. Our observations suggest that oncogenic hijacking of developmental transcription factors can dysregulate transcription through widespread effects on the spatial organization of cancer genomes.

cancer biology↗

bioRxiv2019

Identification of frequent activating HER2 mutations in primary canine pulmonary adenocarcinoma

Naturally occurring primary canine lung cancers are aggressive malignancies that are increasingly common in pet dogs. They share clinicopathologic features with human lung cancers in never-smokers, but their genetic underpinnings are unknown. Through multi-platform sequencing of 88 primary canine lung tumors or cell lines, we discovered somatic, coding HER2 (ERRB2) point mutations in 38% of canine pulmonary adenocarcinomas (cPAC, 28/74), but none in adenosquamous (cPASC, 0/11) or squamous cell (cPSCC, 0/3) carcinomas. In cPASC, PTEN was the most frequently mutated gene (18%) while one case each bore likely pathogenic HRAS, KRAS, EGFR, MET, TP53, or VHL somatic mutations. In cPSCC, no recurrently mutated genes were identified, but individual somatic coding mutations were found in BRAF and PTPN11. In cPAC, we also identified recurrent somatic mutation of TP53 (13.5%), SMAD4 (5.4%), PTEN (4.1%), and VHL (2.7%). cPACs assessed by exome sequencing displayed a low somatic mutation burden (median 64 point mutations, 19 focal copy number variants, and 1 translocation). The majority (93%) of HER2 mutations were hotspot V659E transmembrane domain (TMD) mutations comparable to activating mutations at this same site in human cancer. Other HER2 mutations identified in this study were located in the extracellular domain and TMD. HER2V659E was detected in the plasma of 33% (2/6) of dogs with localized HER2V659E tumors. HER2V659E correlated with constitutive phosphorylation of AKT in cPAC cell lines and HER2V659E lines displayed hypersensitivity to the HER2 inhibitors lapatinib and neratinib relative to HER2-wild-type cell lines. These findings have translational and comparative relevance for lung cancer and HER2 inhibition.

cancer biology↗

bioRxiv2019

RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma

Alterations of the retinoblastoma and/or the p53 signaling network are associated with specific cancers such as high-grade astrocytoma/glioblastoma, small cell lung cancer (SCLC), choroid plexus tumors and small-cell pancreatic neuroendocrine carcinoma (SC-PaNEC). However, the intricate functional compensation between RB1 and the related pocket proteins RBL1/p107 and RBL2/p130 in suppressing tumorigenesis remains poorly understood. Here we performed lineage-restricted parallel inactivation of rb1 and rbl1 by multiplex CRISPR/Cas9 genome editing in the true diploid Xenopus tropicalis to gain insight into these in vivo compensatory mechanisms. We show that while rb1 inactivation is sufficient to induce choroid plexus papilloma, combined rb1 and rbl1 inactivation is required and sufficient to drive SC-PaNEC, retinoblastoma and astrocytoma. Further, using a novel Li-Fraumeni syndrome-mimicking tp53 mutant X. tropicalis line, we demonstrate increased malignancy of retinoblastoma-mutant neural malignancies upon concomitant inactivation of tp53. Interestingly, although clinical SC-PaNEC samples are characterized by abnormal p53 expression or localization, in the current experimental models, the tp53 status had little effect on the establishment and growth of SC-PaNEC, but may rather be essential for maintaining chromosomal stability. SCLC was only rarely observed in our experimental set-up, indicating requirement of additional or alternative oncogenic insults. In conclusion, we used CRISPR/Cas9 to delineate the tumor suppressor properties of Rbl1 and generate new insights in functional compensation within the retinoblastoma protein family in suppressing pancreatic and specific neural cancers.

cancer biology↗

bioRxiv2019

The Evolution of Placental Invasion and Cancer Metastasis are Causally Linked

Among mammals, the extent of placental invasion is correlated with vulnerability to malignancy. Animals with more invasive placentation (e.g. humans) are more vulnerable to malignancy, whereas animals with a non-invasive placenta (e.g. ruminants) are less likely to develop malignant cancer. To explain this correlation, we propose the hypothesis of Evolved Levels of Invasibility (ELI) positing that the permissiveness of stromal tissue to invasion is a unitary character affecting both placental and cancer invasion. We provide evidence for this hypothesis by contrasting invasion of human and bovine cancer and placental cells into a lawn of stromal cells from different species. We find that both bovine endometrial and skin fibroblasts are more resistant to invasion of placental and cancer cells than their human counterparts. Gene expression profiling identified genes with high expression in human but not bovine fibroblasts. Knocking down of a subset of them in human fibroblasts leads to significantly stronger resistance to cancer cell invasion. Comparative analysis of gene expression among mammals suggests that humans evolved higher vulnerability to malignancy than the eutherian ancestor, possibly as a correlate of more invasive placentation, and boroeutherians evolved to decrease stromal invasibility. Identifying the evolutionary determinants of stromal invasibility can provide significant insights to develop rational anti-metastatic therapeutics.

cancer biology↗