scholarly journals On measuring selection in cancer from subclonal mutation frequencies

2019 ◽  
Author(s):  
Ivana Bozic ◽  
Chay Paterson ◽  
Bartlomiej Waclaw
Keyword(s):  
Cancer Progression ◽  
Treatment Strategies ◽  
Intermediate Frequency ◽  
Neutral Evolution ◽  
Relevant Parameter ◽  
Cancer Evolution ◽  
Sequencing Data ◽  
Novel Treatment Strategies ◽  
Subclonal Mutation ◽  
Expanding Population

ABSTRACTRecently available cancer sequencing data have revealed a complex view of the cancer genome containing a multitude of mutations, including drivers responsible for cancer progression and neutral passengers. Measuring selection in cancer and distinguishing drivers from passengers have important implications for development of novel treatment strategies. It has recently been argued that a third of cancers are evolving neutrally, as their mutational frequency spectrum follows a 1/f power law expected from neutral evolution in a particular intermediate frequency range. We study a stochastic model of cancer evolution and derive a formula for the probability distribution of the cancer cell frequency of a subclonal driver, demonstrating that driver frequency is biased towards 0 and 1. We show that it is difficult to capture a driver mutation at an intermediate frequency, and thus the calling of neutrality due to a lack of such driver will significantly overestimate the number of neutrally evolving tumors. Our approach provides precise quantification of the validity of the 1/f statistic across the entire range of all relevant parameter values. Our results are also applicable to the question of distinguishing driver and passenger mutations in a general exponentially expanding population.

Opposing Evolutionary Pressures Drive Clonal Evolution and Health Outcomes in the Aging Blood System

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-37
Author(s):  
Kimberly Skead ◽  
Armande Ang Houle ◽  
Sagi Abelson ◽  
Marie-Julie Fave ◽  
Boxi Lin ◽  
...  
Keyword(s):  
Gene Disruption ◽  
Large Scale ◽  
Evolutionary Dynamics ◽  
Clonal Evolution ◽  
Neutral Evolution ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Sequencing Data ◽  
High Coverage ◽  
Passenger Mutations

The age-associated accumulation of somatic mutations and large-scale structural variants (SVs) in the early hematopoietic hierarchy have been linked to premalignant stages for cancer and cardiovascular disease (CVD). However, only a small proportion of individuals harboring these mutations progress to disease, and mechanisms driving the transformation to malignancy remains unclear. Hematopoietic evolution, and cancer evolution more broadly, has largely been studied through a lens of adaptive evolution and the contribution of functionally neutral or mildly damaging mutations to early disease-associated clonal expansions has not been well characterised despite comprising the majority of the mutational burden in healthy or tumoural tissues. Through combining deep learning with population genetics, we interrogate the hematopoietic system to capture signatures of selection acting in healthy and pre-cancerous blood populations. Here, we leverage high-coverage sequencing data from healthy and pre-cancerous individuals from the European Prospective Investigation into Cancer and Nutrition Study (n=477) and dense genotyping from the Canadian Partnership for Tomorrow's Health (n=5,000) to show that blood rejects the paradigm of strictly adaptive or neutral evolution and is subject to pervasive negative selection. We observe clear age associations across hematopoietic populations and the dominant class of selection driving evolutionary dynamics acting at an individual level. We find that both the location and ratio of passenger to driver mutations are critical in determining if positive selection acting on driver mutations is able to overwhelm regulated hematopoiesis and allow clones harbouring disease-predisposing mutations to rise to dominance. Certain genes are enriched for passenger mutations in healthy individuals fitting purifying models of evolution, suggesting that the presence of passenger mutations in a subset of genes might confer a protective role against disease-predisposing clonal expansions. Finally, we find that the density of gene disruption events with known pathogenic associations in somatic SVs impacts the frequency at which the SV segregates in the population with variants displaying higher gene disruption density segregating at lower frequencies. Understanding how blood evolves towards malignancy will allow us to capture cancer in its earliest stages and identify events initiating departures from healthy blood evolution. Further, as the majority of mutations are passengers, studying their contribution to tumorigenesis, will unveil novel therapeutic targets thus enabling us to better understand patterns of clonal evolution in order to diagnose and treat disease in its infancy. Disclosures Dick: Bristol-Myers Squibb/Celgene: Research Funding.

scholarly journals Myeloid-Derived Suppressor Cells and Therapeutic Strategies in Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Hiroshi Katoh ◽  
Masahiko Watanabe
Keyword(s):  
T Cells ◽  
Cancer Progression ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Suppressor Cells ◽  
Response To Treatment ◽  
Solid Cancer ◽  
Myeloid Derived Suppressor Cells ◽  
Immune Cell Population ◽  
Novel Treatment Strategies

Development of solid cancer depends on escape from host immunosurveillance. Various types of immune cells contribute to tumor-induced immune suppression, including tumor associated macrophages, regulatory T cells, type 2 NKT cells, and myeloid-derived suppressor cells (MDSCs). Growing body of evidences shows that MDSCs play pivotal roles among these immunosuppressive cells in multiple steps of cancer progression. MDSCs are immature myeloid cells that arise from myeloid progenitor cells and comprise a heterogeneous immune cell population. MDSCs are characterized by the ability to suppress both adaptive and innate immunities mainly through direct inhibition of the cytotoxic functions of T cells and NK cells. In clinical settings, the number of circulating MDSCs is associated with clinical stages and response to treatment in several cancers. Moreover, MDSCs are reported to contribute to chemoresistant phenotype. Collectively, targeting MDSCs could potentially provide a rationale for novel treatment strategies in cancer. This review summarizes recent understandings of MDSCs in cancer and discusses promissing clinical approaches in cancer patients.

scholarly journals Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade

2021 ◽  
Vol 22 (6) ◽  
pp. 2844
Author(s):  
Alena Mickova ◽  
Gvantsa Kharaishvili ◽  
Daniela Kurfurstova ◽  
Mariam Gachechiladze ◽  
Milan Kral ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Therapy Resistance ◽  
Mesenchymal Transition ◽  
Slug Expression ◽  
Chemical Inhibition ◽  
Novel Treatment Strategies ◽  
E Cadherin

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.

scholarly journals Novel Strategies for Cancer Treatment: Highlights from the 55th IACR Annual Conference

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1125 ◽  
Author(s):  
Sara Charmsaz ◽  
Denis Collins ◽  
Antoinette Perry ◽  
Maria Prencipe
Keyword(s):  
Cancer Research ◽  
Cancer Progression ◽  
Treatment Strategies ◽  
Tumour Microenvironment ◽  
Annual Conference ◽  
Cancer Treatments ◽  
Novel Technologies ◽  
Combination Treatments ◽  
Novel Treatment Strategies ◽  
Novel Therapeutic Strategies

While conventional cancer treatments, such as surgery, radiotherapy and chemotherapy, have been combined for decades in an effort to treat cancer patients, the emergence of novel fields of cancer research have led to a renewed interest in combining conventional treatments with more innovative approaches. The realisation that cancer progression is not exclusively due to changes in the cancer epithelial cells, but also involves changes in the tumour microenvironment, has opened new avenues for combination treatments. Here we discuss the use of combination therapies presented at the 55th Irish Association for Cancer Research (IACR) Annual Conference, highlighting examples of novel therapeutic strategies which, combined with conventional therapies, may greatly enhance not only the overall outcome for patients, but also the quality of life for cancer survivors. Among the novel treatment strategies, immune metabolism, epigenetic therapies and physical exercise are presented. In addition, novel technologies in the field of precision medicine, which will be useful to discover new therapeutics and to stratify patients for combination treatments, are also discussed.

scholarly journals Clinically Translatable Approaches of Inhibiting TGF-β to Target Cancer Stem Cells in TNBC

2021 ◽  
Author(s):  
Andrew Sulaiman ◽  
Sarah McGarry ◽  
Sai Charan Chilumula ◽  
Vishak Vinod ◽  
Rohith Kandunuri
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Treatment Strategies ◽  
Major Barrier ◽  
Differential Signal ◽  
Growth Factor Beta ◽  
Novel Treatment Strategies ◽  
Patient Prognosis

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that disproportionally accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. In this review, we highlight the complexity of the transforming growth factor-beta family (TGF-β) pathway and discuss how the dysregulation of the TGF-β pathway promotes oncogenic attributes in TNBC which negatively affects patient prognosis. Moreover, we discuss recent findings highlighting TGF-β inhibition as a potent method to target mesenchymal (CD44+/CD24-) and epithelial (ALDHhigh) cancer stem cell (CSC) populations. CSCs are associated with tumorigenesis, metastasis, relapse, resistance, and diminished patient prognosis; however, due to differential signal pathway enrichment and plasticity, these populations remain difficult to target and persist as a major barrier barring successful therapy. This review highlights the importance of TGF-β as a driver of chemoresistance, radioresistance and reduced patient prognosis in breast cancer and highlights novel treatment strategies which modulate TGF-β, impede cancer progression and reduce the rate of resistance generation via targeting the CSC populations in TNBC and thus reducing tumorigenicity. Potential TGF-β inhibitors targeting based on clinical trials are summarized for further investigation which may lead to the development of novel therapies to improve TNBC patient prognosis.

scholarly journals Breast Cancer Stem Cell-Derived ANXA6-Containing Exosomes Sustain Paclitaxel Resistance and Cancer Aggressiveness in Breast Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Zihe Guo ◽  
Ayao Guo ◽  
Chuang Zhou
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Treatment Strategies ◽  
Dependent Manner ◽  
Promote Cell Migration ◽  
Cancer Aggressiveness ◽  
Novel Treatment Strategies ◽  
Underlying Mechanisms

Continuous chemotherapy pressure-elicited annexin-A6 (ANXA6)-containing exosome (ANXA6-exo) secretion contributes to paclitaxel (PTX) resistance in breast cancer (BC), but the molecular mechanisms are not fully elucidated. The present study managed to investigate this issue and found that ANXA6-exo promoted PTX resistance and cancer progression in BC cells in a Yes-associated protein 1 (YAP1)-dependent manner. Specifically, the parental PTX-sensitive BC (PS-BC) cells were exposed to continuous low-dose PTX to generate PTX-resistant BC (PR-BC) cells, and we found that BC stem cells tended to be enriched in the descendent PR-BC cells in contrast with the PS-BC cells. In addition, PR-BC cell-derived exosomes were featured with highly expressed ANXA6, and ANXA6-exo delivered ANXA6 to promote cell migration, growth, autophagy, and stemness in PS-BC cells. Interestingly, ANXA6-exo increased PTX resistance in PS-BC cells via inducing autophagy, and the effects of ANXA6-exo on PTX resistance in PS-BC cells were abrogated by co-treating cells with the autophagy inhibitor 3-methyladenine. Moreover, the underlying mechanisms were uncovered, and we evidenced that ANXA6-exo up-regulated YAP1 to promote Hippo pathway dysregulation, and the promoting effects of ANXA6-exo on PTX resistance and cancer aggressiveness in BC cells were abrogated by silencing YAP1. Taken together, this study firstly elucidated the underlying mechanisms by which BCSC-derived ANXA6-exo facilitated BC progression and PTX resistance, which might help to develop novel treatment strategies for BC in clinic.

scholarly journals Clinically Translatable Approaches of Inhibiting TGF-β to Target Cancer Stem Cells in TNBC

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1386
Author(s):  
Andrew Sulaiman ◽  
Sarah McGarry ◽  
Sai Charan Chilumula ◽  
Rohith Kandunuri ◽  
Vishak Vinod
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Treatment Strategies ◽  
Major Barrier ◽  
Differential Signal ◽  
Growth Factor Beta ◽  
Novel Treatment Strategies ◽  
Patient Prognosis

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that disproportionally accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. In this review, we highlight the complexity of the transforming growth factor-beta family (TGF-β) pathway and discuss how the dysregulation of the TGF-β pathway promotes oncogenic attributes in TNBC, which negatively affects patient prognosis. Moreover, we discuss recent findings highlighting TGF-β inhibition as a potent method to target mesenchymal (CD44+/CD24−) and epithelial (ALDHhigh) cancer stem cell (CSC) populations. CSCs are associated with tumorigenesis, metastasis, relapse, resistance, and diminished patient prognosis; however, due to differential signal pathway enrichment and plasticity, these populations remain difficult to target and persist as a major barrier barring successful therapy. This review highlights the importance of TGF-β as a driver of chemoresistance, radioresistance and reduced patient prognosis in breast cancer and highlights novel treatment strategies which modulate TGF-β, impede cancer progression and reduce the rate of resistance generation via targeting the CSC populations in TNBC and thus reducing tumorigenicity. Potential TGF-β inhibitors targeting based on clinical trials are summarized for further investigation, which may lead to the development of novel therapies to improve TNBC patient prognosis.

scholarly journals Detecting repeated cancer evolution in human tumours from multi-region sequencing data

2017 ◽  
Author(s):  
Giulio Caravagna ◽  
Ylenia Giarratano ◽  
Daniele Ramazzotti ◽  
Trevor A Graham ◽  
Guido Sanguinetti ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Phylogenetic Trees ◽  
Evolutionary Process ◽  
Cancer Evolution ◽  
Sequencing Data ◽  
Robust Identification ◽  
Genomic Changes ◽  
Evolutionary Trajectories ◽  
Genomic Aberrations ◽  
Repeated Evolution

AbstractCarcinogenesis is an evolutionary process driven by the accumulation of genomic aberrations. Recurrent sequences of genomic changes, both between and within patients, reflect repeated evolution that is valuable for anticipating cancer progression. Multi-region sequencing and phylogenetic analysis allow inference of the partial temporal order of genomic changes within a patient’s tumour. However, the inherent stochasticity of the evolutionary process makes phylogenetic trees from different patients appear very distinct, preventing the robust identification of recurrent evolutionary trajectories. Here we present a novel quantitative method based on a machine learning approach called Transfer Learning (TL) that allows overcoming the stochastic effects of cancer evolution and highlighting hidden recurrences in cancer patient cohorts. When applied to multi-region sequencing datasets from lung, breast and renal cancer (708 samples from 160 patients), our method detected repeated evolutionary trajectories that determine novel patient subgroups, which reproduce in large singlesample cohorts (n=2,641) and have prognostic value. Our method provides a novel patient classification measure that is grounded in the cancer evolution paradigm, and which reveals repeated evolution during tumorigenesis, with implications for our ability to anticipate malignant evolution.

scholarly journals Clinically Translatable Approaches of Inhibiting TGF-β to Target Cancer Stem Cells in TNBC

2021 ◽  
Author(s):  
Andrew Sulaiman ◽  
Sarah McGarry ◽  
Sai Chilumula ◽  
Rohithk Kandunuri ◽  
Vishak Vinod
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Treatment Strategies ◽  
Major Barrier ◽  
Differential Signal ◽  
Popula Tions ◽  
Novel Treatment Strategies ◽  
Patient Prognosis

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that disproportionally accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. In this review, we highlight the complexity of the transforming growth factor-beta family (TGF-β) pathway and discuss how the dysregulation of the TGF-β pathway promotes oncogenic attributes in TNBC which negatively affects patient prognosis. Moreover, we discuss recent findings highlighting TGF-β inhibition as a potent method to target mesenchymal (CD44+/CD24-) and epithelial (ALDHhigh) cancer stem cell (CSC) populations. CSCs are associated with tumorigenesis, metastasis, relapse, resistance, and diminished patient prognosis; however, due to differential signal pathway enrichment and plasticity, these popula-tions remain difficult to target and persist as a major barrier barring successful therapy. This review highlights the importance of TGF-β as a driver of chemoresistance, radioresistance and reduced patient prognosis in breast cancer and discusses novel treatment strategies which modulate TGF-β, impede cancer progression and reduce the rate of resistance generation via targeting the CSC populations in TNBC and thus reducing tumorigenicity. Potential TGF-β inhibitors targeting based on clinical trials are summarized for further investigation which may lead to the development of novel therapies to improve TNBC patient prognosis.

scholarly journals FROM EMERGING BIOLOGICAL INSIGHTS TO NOVEL TREATMENT STRATEGIES IN PROSTATE CANCER

2014 ◽  
Author(s):  
Patrizia Limonta ◽  
Roberta M. Moretti ◽  
Stefania Mai ◽  
Monica Marzagalli ◽  
Marcella Motta ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Initial Phase ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Gnrh Agonists ◽  
Castration Resistance ◽  
Gnrh Receptors ◽  
Novel Treatment Strategies ◽  
Novel Therapeutic Strategies

Prostate cancer is androgen-dependent in its initial phase. GnRH agonists, through desensitization of pituitary GnRH receptors and subsequent suppression of testosterone secretion, represent the therapy of choice for this pathology. After an initial phase of remission, prostate cancer progresses towards its most aggressive phase of castration-resistance (CRPC). Since conventional chemotherapy treatments (i.e., docetaxel) have provided scant benefit, the identification of the molecular mechanisms underlying prostate cancer progression will definitely help increase the therapeutic options for this almost incurable pathology. Receptors for GnRH agonists are expressed in CRPC cells and their activation significantly inhibit the proliferative and the metastatic behavior of cancer cells, and interferes with the angiogenic process. These data support the notion that locally expressed GnRH receptors represent an effective molecular target for novel therapeutic strategies for CRPC.

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