Biology subjects

Maley, C. C.

Publications and source records attributed to Maley, C. C..

At least 19 recordsLinked to original sources

bioRxiv2026

PHYFUM: Phylogenetic Reconstruction of Normal and Pre-malignant Tissue Evolution Using Fluctuating Methylation

We present PHYFUM, a novel Bayesian phylogenetic method for methylation data that reconstructs the evolutionary history of stem cells and the glandular structures they reside within in normal tissue. Using simulations, we validated this phylogenetic method and confirmed its accuracy. A re-analysis of 22 patients unveiled early gland divergence in the human gut, in contrast to a much later common ancestor in the endometrium, and yielded strong evidence against gland division by segregation of individual stem cells.

bioinformatics↗

bioRxiv2025

A Systematic Review of Evidence for the Cost of Therapeutic Resistance in Cancer

Emergence of therapeutic resistance is a critical clinical challenge in cancer treatment, contributing to treatment failure, disease relapse, and patient mortality. Prior to treatment initiation, therapy-resistant clones typically make up such a small proportion of the neoplasm that they can be hard to detect and only expand under the selective pressure of therapy. This suggests that resistant clones incur a fitness cost for resistance to therapy. Whether therapeutic resistance incurs a fitness cost has important clinical implications, including the potential to leverage competition with sensitive cells to prevent the expansion of the resistant population. However, the fitness compromises associated with treatment resistance in cancer are not well-understood at present. We conducted a systematic review for peer-reviewed papers that fulfilled the following selection criteria: (i) experiments depict direct competition, (ii) between therapy-resistant and therapy-sensitive clones, (iii) in an untreated environment. We found 49 experiments that matched those criteria, of which approximately two-thirds found a fitness cost to resistance in a competitive environment. Of all pooled features, we found that the resistance characteristic was most significantly associated with whether resistant clones exhibited a fitness advantage in competition (p=0.0154). Further, we identify complex ecological interactions that may influence the behavior of the cancer cell population in the untreated environment. Predicting which resistance characteristics can be exploited therapeutically and identifying potential methods of modulating the costliness of the resistant phenotype may be critical to future improvements in cancer therapy. Lay SummaryWhen cancer cells evolve to no longer respond to a cancer therapy, do they pay a cost for that invulnerability? We reviewed experiments where cancer cells resistant to a therapy were pitted against cancer cells that were still sensitive to the therapy. Approximately [2/3] of the experiments showed that the sensitive cells could out-compete the resistant cells, implying that the latter were paying some cost for their ability to resist the therapy.

cancer biology↗

bioRxiv2025

Does Fermentation Enhance Beverage Safety? Kombucha's Resistance to Microbial Invasion Suggests a Protective Role

Does fermentation enhance the safety of beverages? This study investigates kombuchas resilience to microbial invasion from human hands. Kombucha, an ancient fermented tea, relies on a biofilm known as a symbiotic community of bacteria and yeast (SCOBY) and a starter culture to ferment sweet tea, producing various metabolites including gluconic acid, acetic acid, ethanol, and carbon dioxide. While fermented foods have been historically associated with potential health benefits, direct evidence comparing the prevalence of human pathogens in fermented versus non-fermented beverages has been lacking. To address this, we conducted a citizen science experiment at Arizona State University, introducing swabs from peoples palms into both kombucha and a sweet tea control. Over 30 days, we monitored the bacterial and fungal composition using 16S and ITS rRNA sequencing. Our findings reveal that kombucha maintained a relatively stable microbial profile and physical appearance, with a typical SCOBY biofilm developing. In stark contrast, the sweet tea experienced a dramatic change in microbial composition and was visibly compromised by rapidly growing microorganisms. Importantly, this suggests that the complex microbial ecosystem of kombucha can limit the growth of foreign microbes introduced from human hands. Given that human pathogens were absent from the kombucha while present in the tea samples, our results indicate that the antimicrobial properties of fermentation byproducts and the physical barrier of the SCOBY may contribute to this resilience. Further research is warranted to fully elucidate the mechanisms underlying kombuchas resistance to microbial invasion.

microbiology↗

bioRxiv2025

Immune-cancer analyses across mammals reveal a potential trophic level and platelet-linked tradeoff between cancer and trauma mortality

There may be fitness tradeoffs between wound healing, immune responses, and cancer development due to shared pathways, limited resources and conflicting selective pressures. The immune system is important in both response to injury and carcinogenesis. We initially investigated correlations between cancer prevalence and immune cells, controlling for known associations with body mass and lifespan. We analyzed data from 216 mammalian species from at least 20 individuals per species. Body mass correlated positively with segmented neutrophil-to-lymphocyte ratios and negatively with lymphocyte concentrations. However, only platelet concentration correlated (negatively) with cancer prevalence (P-value = 0.006). To further understand this association, we investigated whether a fitness tradeoff could exist between preventing death from cancer versus injury. We discovered a negative correlation between cancer and trauma mortalities (P-value [≤] 0.0006), even when we accounted for the fact that different causes of death must sum to 100%. Platelet size and trophic level negatively correlated with trauma mortality, but not when controlling for cancer mortality (P-value = 0.06). If trauma mortality is an indirect measure of wound healing, this suggests a fitness tradeoff may exist between cancer suppression and wound healing across mammals, mediated in part through platelet size and trophic level.

evolutionary biology↗

bioRxiv2025

Spatial Conformation of Pancreatic Cancer Is Associated with Disease Recurrence after Curative-Intent Total Neoadjuvant Therapy

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after total neoadjuvant therapy (TNT) and curative-intent resection. Traditional histopathologic response assessments demonstrate that major pathologic response (<5-10% viable residual cancer) is associated with favorable outcomes. However, most TNT cases achieve only a minor response. We investigated whether the spatial organization of residual PDAC encodes clinically meaningful biology beyond residual tumor burden. In a retrospective cohort of 203 resected PDAC patients, all with minor pathologic response, H&E whole-slide images were segmented into cancer and stroma to subsequently quantify spatial composition (e.g., patch size/density, edge density) and configuration (e.g., patch complexity/compactness, spatial intermixing) to model treatment-resistant tumor architecture. Non-response was associated with a more fragmented interface-rich ecology, higher edge density and diversity, and reduced homotypic aggregation, independent of conventional clinicopathologic features. This demonstrates a link between emergent tissue architecture of treated PDAC and therapeutic resistance. Further, two multivariable, spatial risk models were independently associated with disease-free survival (DFS): (1) cancer mean shape index and stromal shape-index variability (high-risk median DFS 7.23 vs 11.57 months; adjusted HR 1.75, p=0.007) and (2) mean stromal area with edge density (high- vs low-risk adjusted HR 1.94, p=0.006), outperforming traditional treatment response assessments. Quantifying residual cancer-stroma topology thus yields independent, prognostic signals in post-TNT PDAC and motivates prospective, spatially informed adjuvant strategies and mechanistic studies of edge habitats and mixing as therapeutic vulnerabilities.

cancer biology↗

bioRxiv2025

Tumor Landscape Analysis: An Ecologically Informed Framework to Understand Tumor Microenvironments

Tumor microenvironments (TMEs) are spatially complex and dynamic systems shaped by evolutionary pressures, tissue architecture, and cellular interactions. To capture this complexity, we developed the Tumor Landscape Analysis (TLA) pipeline, a computational framework applying principles from landscape ecology and spatial statistics to quantitatively characterize tumor spatial heterogeneity. TLA integrates spatially resolved pathology data, including whole-cell, point-based, and region-level formats, and computes multiscale metrics to assess cell distributions, neighborhood relationships, and tissue-level organization. The framework leverages ecological indices such as the Morisita-Horn index, Ripleys H function, and Shannon diversity to quantify intercellular proximity, spatial clustering, and cellular diversity. It also uses the concept of local microenvironments (LMEs), data-driven ecological niches defined by local cell-type abundance and spatial uniformity, enabling unsupervised and reproducible classification of tumor regions. The use of fragmentation metrics, including patch density, shape complexity, and interspersion, provide further insight into spatial disorganization and emergent tissue architecture. TLA is agnostic to imaging modality and biological context, supporting broad applicability across tumor types and sample formats. By translating complex tissue architectures into interpretable spatial metrics, the pipeline enables integrative analyses that link spatial ecology to clinical and molecular phenotypes. This approach facilitates a deeper understanding of how spatial features contribute to tumor progression, therapeutic resistance, and clinical outcomes, offering new opportunities for precision oncology rooted in spatial systems biology.

cancer biology↗

bioRxiv2025

Leveraging Comparative Phylogenetics for Evolutionary Medicine: Applications to Comparative Oncology

Comparative phylogenetics provides a wealth of computational tools to understand evolutionary processes and their outcomes. Advances in these methodologies have occurred in parallel with a surge in cross-species genomic and phenotypic data. To date, however, the majority of published studies have focused on classical questions in evolutionary biology, such as speciation and the ecological drivers of trait evolution. Here, we argue that evolutionary medicine in general, and our understanding of the origin and diversification of disease traits in particular, would be greatly expanded by a wider integration of phylogenetic comparative methods (PCMs). We use comparative oncology - the study of cancer across the tree of life - as a case study to demonstrate the power of the approach and show that implementing PCMs can highlight the mode and tempo of the evolutionary changes in intrinsic, species-level disease vulnerabilities.

evolutionary biology↗

bioRxiv2024

Epigenome and early selection determine the tumour-immune evolutionary trajectory of colorectal cancer

Immune system control is a major hurdle that cancer evolution must circumvent. The relative timing and evolutionary dynamics of subclones that have escaped immune control remain incompletely characterized, and how immune-mediated selection shapes the epigenome has received little attention. Here, we infer the genome- and epigenome-driven evolutionary dynamics of tumour-immune coevolution within primary colorectal cancers (CRCs). We utilise our existing CRC multi-region multi-omic dataset that we supplement with high-resolution spatially-resolved neoantigen sequencing data and highly multiplexed imaging of the tumour microenvironment (TME). Analysis of somatic chromatin accessibility alterations (SCAAs) reveals frequent somatic loss of accessibility at antigen presenting genes, and that SCAAs contribute to silencing of neoantigens. We observe that strong immune escape and exclusion occur at the outset of CRC formation, and that within tumours, including at the microscopic level of individual tumour glands, additional immune escape alterations have negligible consequences for the immunophenotype of cancer cells. Further minor immuno-editing occurs during local invasion and is associated with TME reorganisation, but that evolutionary bottleneck is relatively weak. Collectively, we show that immune evasion in CRC follows a "Big Bang" evolutionary pattern, whereby genetic, epigenetic and TME-driven immune evasion acquired by the time of transformation defines subsequent cancer-immune evolution.

cancer biology↗

bioRxiv2023

Growth Dynamics of Ductal Carcinoma in Situ Recapitulate Normal Breast Development

Ductal carcinoma in situ (DCIS) and invasive breast cancer share many morphologic, proteomic, and genomic alterations. Yet in contrast to invasive cancer, many DCIS tumors do not progress and may remain indolent over decades. To better understand the heterogenous nature of this disease, we reconstructed the growth dynamics of 18 DCIS tumors based on the geo-spatial distribution of their somatic mutations. The somatic mutation topographies revealed that DCIS is multiclonal and consists of spatially discontinuous subclonal lesions. Here we show that this pattern of spread is consistent with a new Comet model of DCIS tumorigenesis, whereby multiple subclones arise early and nucleate the buds of the growing tumor. The discontinuous, multiclonal growth of the Comet model is analogous to the branching morphogenesis of normal breast development that governs the rapid expansion of the mammary epithelium during puberty. The branching morphogenesis-like dynamics of the proposed Comet model diverges from the canonical model of clonal evolution, and better explains observed genomic spatial data. Importantly, the Comet model allows for the clinically relevant scenario of extensive DCIS spread, without being subjected to the selective pressures of subclone competition that promote the emergence of increasingly invasive phenotypes. As such, the normal cell movement inferred during DCIS growth provides a new explanation for the limited risk of progression in DCIS and adds biologic rationale for ongoing clinical efforts to reduce DCIS overtreatment.

cancer biology↗

bioRxiv2023

Testing Adaptive Therapy Protocols using Gemcitabine and Capecitabine on a Mouse Model of Endocrine-Resistant Breast Cancer

Highly effective cancer therapies often face limitations due to acquired resistance and toxicity. Adaptive therapy, an ecologically inspired approach, seeks to control therapeutic resistance and minimize toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life over maximum cell kill. In preparation for a clinical trial in breast cancer, we used large populations of MCF7 cells to rapidly generate endocrine-resistance breast cancer cell line. We then mimicked second line therapy in ER+ breast cancers by treating the endocrine-resistant MCF7 cells in a mouse xenograft model to test adaptive therapy with capecitabine, gemcitabine, or the combination of those two drugs. Dose-modulation adaptive therapy with capecitabine alone increased survival time relative to MTD, but not statistically significant (HR: 0.22, 95% CI 0.043-1.1 P = 0.065). However, when we alternated the drugs in both dose modulation (HR = 0.11, 95% CI: 0.024 - 0.55, P = 0.007) and intermittent adaptive therapies significantly increased survival time compared to high dose combination therapy (HR = 0.07, 95% CI: 0.013 - 0.42; P = 0.003). Overall, survival time increased with reduced dose for both single drugs (P < 0.01) and combined drugs (P < 0.001). Adaptive therapy protocols resulted in tumors with lower proportions of proliferating cells (P = 0.0026) and more apoptotic cells (P = 0.045). The results show that Adaptive therapy outperforms high-dose therapy in controlling endocrine-resistant breast cancer, favoring slower-growing tumors, and showing promise in two-drug alternating regimens.

cancer biology↗

bioRxiv2023

Germline mutation rate predicts cancer mortality across 37 vertebrate species

The explanation for why some species are more susceptible to cancer than others remains an area of intense investigation. Cancer evolves in part through the accumulation of mutations and, therefore, we hypothesized that germline mutation rates would be associated with cancer prevalence and mortality across species. We collected previously published data on germline mutation rate and cancer mortality data for 37 vertebrate species. Germline mutation rate was positively correlated with cancer mortality (P = 0.008). Why animals with increased germline mutation rates die more from cancer remains an open question, however they may benefit from close monitoring for tumors due to hereditary cancer predisposition syndromes. Early diagnoses of cancer in these species may increase their chances of treatment and overall survival.

cancer biology↗

bioRxiv2023

The relationship between diet, plasma glucose, and cancer prevalence across vertebrates

Could diet and mean plasma glucose concentration (MPGluC) explain the variation in cancer prevalence across species? We collected diet, MPGluC, and neoplasia data for 160 vertebrate species from existing databases. We found that MPGluC negatively correlates with cancer and neoplasia prevalence, mostly of gastrointestinal organs. Trophic level positively correlates with cancer and neoplasia prevalence even after controlling for species MPGluC. Most species with high MPGluC (50/78 species = 64.1%) were birds. Most species in high trophic levels (42/53 species = 79.2%) were reptiles and mammals. Our results may be explained by the evolution of insulin resistance in birds which selected for loss or downregulation of genes related to insulin-mediated glucose import in cells. This led to higher MPGluC, intracellular caloric restriction, production of fewer reactive oxygen species and inflammatory cytokines, and longer telomeres contributing to longer longevity and lower neoplasia prevalence in extant birds relative to other vertebrates.

cancer biology↗

bioRxiv2023

In Silico Investigations of Adaptive Therapy Using a Single Cytotoxic or a Single Cytostatic Drug

Adaptive therapy, as per the dose modulation, dose-skipping, or intermittent treatment protocol works well for treatment using a single cytotoxic drug, under a wide range of scenarios and parameter settings. In contrast, adaptive therapy works well only under a limited number of scenarios and parameter settings when using a single cytostatic drug. In general, adaptive therapy works best under conditions of higher fitness cost, higher replacement rate, higher turnover. Adaptive therapy works best when drug dosages are changed as soon as a change in tumor burden is detected. In general, it is better to pause treatment sooner than later, when the tumor is shrinking If the amount of drug used is too low, it is unable to control the sensitive cells and the tumor grows. However, if the drug dose is too high, it quickly selects for resistant cells and eventually the tumor grows out of control. However, there appears to be intermediate levels of dosing, which we call the minimum effective dose, which is able to control the sensitive cells but is not high enough to select for the resistant cells to grow out of control.

bioinformatics↗

bioRxiv2023

In Silico Investigations of Adaptive Therapy Using Two Cytotoxic or Two Cytostatic Drugs

While the dose modulation (DM) protocols (DM Cocktail Tandem, DM Ping-Pong Alternate Every Cycle, DM Ping-Pong on Progression) involves adjusting drug dosages when the tumor burden changes, the fixed-dose (FD) protocols involves administering a specific, constant dosage of the drug only when the tumor is growing (Dose-Skipping) or when the absolute tumor burden is above the baseline level until it reduces to a certain percentage of the baseline (Intermittent). Moreover, two different drugs can be administered simultaneously (cocktail), or the drugs can be switched such that only one drug is applied at a given time (ping-pong), either every cycle (ping-pong alternate every cycle) or when the tumor grows (ping-pong on progression). The dose modulation protocols work well when treated with two cytotoxic drugs, however, the ping-pong protocols (DM Ping-Pong Alternate Every Cycle, DM Ping-Pong on Progression, FD Ping-Pong Intermittent) work well when treated with two cytostatic drugs. In general, adaptive therapy, using either two cytotoxic or two cytostatic drugs works best under conditions of high competition, such as high fitness cost, high replacement rates, and high turnover, although treatment using two cytostatic drugs works best under low turnover in many cases. Adaptive therapy works best when drug dosages are changed as soon as a change in tumor burden is detected, and it is best to pause treatment sooner rather than later when the tumor is shrinking. Adaptive therapy works best when an intermediate level of drug dosage is used, and both treatment with too little or too much drug leads to poor survival outcome.

bioinformatics↗

bioRxiv2023

Life history and cancer in birds: clutch size predicts cancer

Cancer is a disease that affects nearly all multicellular life, including birds. However, little is known about what factors explain the variance in cancer prevalence among species. Litter size is positively correlated with cancer prevalence in managed species of mammals, and larger body size, but not incubation or nestling period, is linked to tumor prevalence in wild birds. Also, birds that produce more elaborate sexual traits are expected to have fewer resources for cancer defenses and thus higher cancer prevalence. In this study, we examined whether cancer prevalence is associated with a wide variety of life history traits (clutch size, incubation length, body mass, lifespan, and the extent of sexual dimorphism) across 108 species of managed birds in 25 different zoological facilities, sanctuaries, and veterinary clinics. We found that clutch size was positively correlated with cancer and neoplasia (both benign and malignant) prevalence, even after controlling for body mass. Cancer prevalence was not associated with incubation length, body mass, lifespan, or sexual dimorphism. The positive correlations of clutch size with cancer prevalence and neoplasia prevalence suggest that there may be life-history trade-offs between reproductive investment and somatic maintenance (in the form of cancer prevention mechanisms) in managed birds.

cancer biology↗

bioRxiv2022

The ecology of cancer prevalence across species: Cancer prevalence is highest in desert species and high trophic levels

The ecology in which species live and evolve likely affects their health and vulnerability to diseases including cancer. Using 14,267 necropsy records across 244 vertebrate species, we tested if animals in low productivity habitats, with large habitat range, high body temperature and weight-inferred estimates of metabolic rates, and in high trophic levels (from lowest to highest: herbivores, invertivores, primary carnivores, and secondary carnivores) are linked with having increased prevalence of neoplasia. This study found that: (1) habitat productivity negatively correlated with the prevalence of malignancy and neoplasia across tissues, and malignancy and neoplasia in gastrointestinal tissues; (2) inferred metabolic rates negatively correlated with the prevalence of neoplasia; and (3) trophic levels positively correlated with malignancy and neoplasia prevalence in both mammals and non-mammals. However, only the correlations with trophic levels remained significant after Bonferroni corrections for multiple testing. There are several mechanisms that might explain these findings, including the biomagnification of carcinogens in higher trophic levels, as well as tradeoffs between cancer suppression versus reproduction and survival in low productivity environments.

cancer biology↗

bioRxiv2022

Extrachromosomal DNA in the cancerous transformation of Barrett's esophagus

BACKGROUNDOncogenes are commonly amplified on extrachromosomal DNA (ecDNA) contributing to poor outcomes for patients. Currently, the chronology of ecDNA development is not known. We studied the origination and evolution of ecDNA in patients with Barretts esophagus (BE) who progressed to esophageal adenocarcinoma (EAC). METHODSWe analyzed whole-genome sequencing (WGS) data from a BE surveillance cohort and EAC patients at Cambridge University UK (n=206 patients). We also analyzed WGS data from biopsies taken at two time points from multiple sites in the esophagus from 80 patients enrolled in a case-control study at the Fred Hutchinson Cancer Center (FHCC) - 40 BE patients who progressed to EAC and 40 who did not. RESULTSecDNA was detected in 24% and 43% of BE patients with BE-associated early and late-stage EAC, respectively, in the Cambridge cross-sectional cohort. ecDNA was found in 33% of all FHCC BE patients who developed cancer, either prior to, or at EAC diagnosis. ecDNA was strongly associated with patients who developed cancer, in contrast with FHCC BE patients who did not progress (odds ratio, 18.8, CI - 2.3-152, p=3.3x10-4). ecDNAs were enriched for oncogenes and immunomodulatory genes and could be detected early in the transition from high-grade dysplasia to cancer and increased in copy number and complexity over time. CONCLUSIONSecDNAs can develop before a diagnosis of cancer in BE patients and are strongly selected for during the evolution to EAC. ecDNAs promote diverse oncogene and immunomodulatory gene amplification during EAC development and progression.

genomics↗

bioRxiv2020

Radiation resistance in Placozoa: Trichoplax adhaerens upregulates DNA repair genes and extrudes cells after exposure.

Trichoplax adhaerens is the simplest multicellular animal with tissue differentiation and somatic cell turnover. Like all other multicellular organisms, it should be vulnerable to cancer, yet there have been no reports of cancer in T. adhaerens, or any other placozoan. We investigated the cancer resistance of T. adhaerens, discovering that they are able to tolerate high levels of radiation damage (218.6 Gy). To investigate how T. adhaerens survive levels of radiation that are lethal to other animals, we examined gene expression after the X-ray exposure, finding overexpression of genes involved in DNA repair and apoptosis including the MDM2 gene. We also discovered that T. adhaerens extrudes clusters of inviable cells after X-ray exposure. T. adhaerens is a valuable model organism for studying the molecular, genetic and tissue-level mechanisms underlying cancer suppression.

cancer biology↗