We have recently described that the most prevalent 100 mutations identified in human cancers, both single nucleotide variations (SNVs) and InDels, generate a handful number of shared mutated neoantigens (SNV and InDel-NeoAgs) in association with 5 HLA-A and 7 B haplotypes.

In the present study, we expanded such analysis to 50 haplotypes in the three MHC class I loci (10 HLA-A, 27 HLA-B and 13 HLA-C), including all the mutated proteins identified in at least 5% of cancer patients.

Overall, the extended analysis identified 15 SNV-NeoAgs and 55 InDel-NeoAgs with a significant affinity improvement over the corresponding wt (DAI > 10). These targetable shared NeoAgs are prevalently derived from PIK3CAH1047R (6/15 SNV-NeoAgs) and LARP4BT163Hfs (30/55 InDel-NeoAgs). From the HLA perspective, the HLA-A*33:03 is associated with the largest number of SNV-NeoAgs (4/15 NeoAgs) and the HLA-B*58:01 is associated with the largest number of InDel-NeoAgs (16/55 NeoAgs). According to the distribution of each HLA haplotype in at least 10% of the regional populations, therapeutic cancer vaccines based on mutated shared SNV and InDel-NeoAgs, might be developed for COAD, STAD and UCEC cancers, with a global coverage, and for PAAD and UVM, with a regional coverage.

This represents the first in-depth analysis for the identification of a specific repertoire of shared mutated NeoAgs, most of which never reported before. Such shared SNV and InDel-NeoAgs are indispensable for the development of "off-the-shelf" cancer vaccines targeting a relevant percentage of cancers in a significant percentage of cancer patients worldwide.

Non-small cell lung cancer (NSCLC) represents the vast majority of lung cancer cases, comprising 80-85% of all diagnoses, and continues to be a primary contributor to cancer-related deaths. Early detection is essential for improving patient outcomes, yet current diagnostic markers lack both sensitivity and specificity. This study aims to identify novel biomarkers that could enhance early diagnosis.

We conducted a comprehensive gene expression analysis of three NSCLC datasets (GSE33479, GSE18842, and GSE32863) and identified seven genes with relevance to the extracellular region and space: MMP11, SPP1, ERO1L, CTHRC1, SPINK1, LAD1, and SFN. We further assessed these markers through serum protein analysis involving 200 NSCLC patients and 200 healthy controls, employing receiver operating characteristic (ROC) curve analysis to evaluate their diagnostic efficacy.

Among the identified genes, MMP11 and SPP1 exhibited significant upregulation and strong discriminatory power in NSCLC tissues, achieving area under the curve (AUC) values exceeding 0.9. Serum protein levels of MMP11 and SPP1 were significantly higher in NSCLC patients compared to healthy controls. ROC curve analysis confirmed the diagnostic potential of MMP11 (AUC: 0.9896) and SPP1 (AUC: 0.9053), both outperforming the existing marker carcinoembryonic antigen (CEA) (AUC: 0.7109). MMP11 demonstrated sensitivity of 94.53% and specificity of 94.97%, while SPP1 showed sensitivity of 83.17% and specificity of 83.84%. In contrast, CEA exhibited a sensitivity of 66.83% and specificity of 67.69%.

The results indicate that MMP11 and SPP1, detectable in serum, may serve as valuable non-invasive biomarkers for the early diagnosis of NSCLC, particularly within health screening contexts. However, further research within larger and more diverse cohorts is imperative to validate these biomarkers and investigate the mechanisms underlying MMP11 and SPP1 expression in NSCLC. This study highlights the potential of these biomarkers to enhance diagnostic accuracy and improve patient outcomes in NSCLC.

In the presence of cellular mutations and impaired mechanisms of energy transmission to the attached cells and tissues, excess energy is available to upregulate some of the mechanotransduction pathways that maintain cell and tissue structure and function. The ability to transfer applied energy through integrin-mediated pathways, cell ion channels, cell membrane, cytoskeleton-nucleoskeleton connections, cell junctions, and cell-extracellular matrix attachments provides an equilibrium for energy storage, transmission, and dissipation in tissues. Disruption in energy storage, transmission, or dissipation via genetic mutations blocks mechanical communication between cells and tissues and impairs the mechanical energy equilibrium that exists between cells and tissues. This results in local structural changes through altered regulatory pathways, which produce cell clustering, collagen encapsulation, and an epithelial-mesenchymal transition (EMT), leading to increased cellular motility along newly reorganized collagen fibers (fibrosis). The goal of this review is to postulate how changes in energy transfer between cells and the extracellular matrix may alter local energy equilibrium and mechanotransduction pathways. The changes along with cellular mutations lead to cell and ECM changes reported in cancer, which is postulated to modify mechanical equilibria between cells and their ECM. This leads to uncontrolled cancer cellular proliferation and collagen remodeling.

The molecular mechanisms through which endometriosis-related ovarian neoplasms (ERONs) develop from benign endometrioma remain unclear. It is especially a long-standing mystery why ovarian endometrioma has the potential to develop into two representative histological subtypes: endometrioid ovarian carcinoma or clear cell ovarian carcinoma. This study aimed to investigate the molecular carcinogenesis of ERONs using newly developed in vitro and in vivo carcinogenesis models. Epithelial cells were isolated and purified from surgically removed benign endometrioma samples, followed by immortalization by overexpressing cyclinD1/CDK4 in combination with the human TERT gene. Immortalized cells were subjected to various molecular manipulations by combining knockout or overexpression of several candidate drivers, including ARID1A, KRAS, PIK3CA, AKT, and MYC, based on previous comprehensive genome-wide studies of ERONs. These cells were then inoculated into immunocompromised mice and evaluated for malignant transformation. Inoculated cells harboring a combination of three genetic alterations successfully developed tumors with malignant features in mice, whereas those with two genetic manipulations failed to do so. Especially, ARID1A gene knockout, combined with overexpressing the KRAS oncogenic mutant allele (or overexpressing AKT) and c-Myc overexpression led to efficient tumor formation. Of note, these three combinations of genetic alterations produced tumors that histologically represented typical clear cell carcinoma in SCID mice, while the same combination led to tumors with endometrioid histology in nude mice. A combination of ARID1A mutation, KRAS mutation or AKT activation, and c-Myc overexpression were confirmed to be the main candidate drivers for the development of ERONs, as suggested by comprehensive genetic analyses of ERONs. A tumor immune microenvironment involving B-cell signaling may contribute to the diverse histological phenotypes. The present model may help to clarify the molecular mechanisms of ERON carcinogenesis and understand their histological diversity and novel molecular targets.

Cancer remains a major global health challenge, with prostate cancer, lung cancer, colorectal cancer, and breast cancer accounting for nearly half of all diagnoses. Despite advancements in cancer treatment, metastasis to distant organs continues to be the leading cause of cancer-related mortality. The progression of cancer involves the alteration of numerous genes, with dynamic changes in chromatin organization and histone modifications playing a critical role in regulating cancer-associated genes. Special AT-rich sequence-binding protein 1 (SATB1), a critical chromatin organizer, plays a pivotal role in cancer progression by regulating gene expression, chromatin remodeling, and cell signaling pathways. SATB1 binds to AT-rich DNA sequences, acting as a scaffold for chromatin-modifying enzymes and transcription factors, thus coordinating the regulation of extensive gene networks. Its overexpression has been implicated in a wide range of cancers and is associated with poor prognosis, aggressive tumor phenotypes, and enhanced epithelial-mesenchymal transition (EMT). Moreover, SATB1's activity is modulated by microRNAs (miRNAs) and post-translational modifications, further contributing to its complex regulatory functions. Given its crucial involvement in cancer progression and metastasis, SATB1 has emerged as a promising target for novel therapeutic strategies. This review delves into the molecular mechanisms of SATB1 in cancer and explores potential therapeutic approaches for targeting this key regulator in cancer treatment.

Mesenchymal stem cells (MSCs) have emerged as crucial players within the tumor microenvironment (TME), contributing through their paracrine secretome. Depending on the context, the MSC-derived secretome can either support or inhibit tumor growth. This study investigates the role of MSC-derived secretome in modulating breast cancer (BC) cell behavior, with a focus on ten-eleven translocation 1 (TET1), a DNA demethylase with known oncogenic properties in triple-negative breast cancer (TNBC). We first isolated and characterized human bone marrow-derived MSCs, and then assessed the impact of their secretome on BC cells. Treatment with the MSC-derived secretome significantly inhibited the proliferation and migration of both MDA-MB-231 and MCF-7 BC cell lines, resulting in reduced cell viability and migration rates compared to control cells. Western blot analyses revealed downregulation of Cyclin D1 and c-Myc, along with decreased expression of N-cadherin and increased expression of E-cadherin, indicating potential inhibition of the epithelial-to-mesenchymal transition. Differential gene expression analyses highlighted TET1 as significantly upregulated in TNBC tissues compared to normal samples. Further experiments confirmed that the MSC-derived secretome downregulated TET1 expression in BC cells, as evidenced by RT-qPCR and western blot analyses. To explore TET1's functional role, we silenced TET1 with siRNAs, observing cell cycle arrest and enhanced apoptosis-effects that mirrored those seen with MSC-secretome treatment. Notably, TET1 knockdown also increased MDA-MB-231 cell sensitivity to cisplatin, suggesting a role for TET1 in chemoresistance. These findings provide insight into the ability of MSCs to modulate BC cell progression through their secretome, highlighting the involvement of TET1 downregulation in inhibiting BC cell progression and enhancing cisplatin chemosensitivity. The MSC-derived secretome thus holds promise as an innovative, cell-free therapeutic approach in BC treatment.

Meningiomas are central nervous system tumors whose incidence increases with age. Benign meningioma pathogenesis involves germline or somatic mutation of target genes, such as NF2, leading to clonal expansion. We used an established cancer epidemiology model to investigate the number of rate-limiting steps sufficient for benign meningioma development.

Incidence data was obtained from the Surveillance, Epidemiology and End Results Program (SEER) for nonmalignant meningioma from 2004 to 2020. Age-adjusted incidence rates per 100,000 person-years were divided into 5-year bands. This was repeated for vestibular schwannomas as a negative control. The Armitage-Doll methodology was applied. Mathematical solutions correcting for volatile tumor microenvironments were applied to fit higher-order models using polynomial regression when appropriate. A 75:25 training:test split was utilized for validation.

222,509 cases of benign meningiomas were identified. We noted strong linear relationships between log-transformed incidence and age across the cohort and multiple subpopulations: male, white, black, Hispanic, Asian/Pacific Islander, and American Indian subpopulations all demonstrated R2 = 0.99. Slopes were between 3.1 and 3.4, suggesting a four-step process for benign meningioma development. Female patients exhibited nonlinear deviations, but the corrected model demonstrated R2 = 0.99 with a four-hit pathway. This model performed robustly on test data with R2 = 0.99. Vestibular schwannomas demonstrated a slope of 2.1 with R2 = 0.99, suggesting a separate three-step process.

Four mutations are uniquely required for the development of benign meningiomas. Correcting for volatile tumor microenvironments reliably accounted for nonlinear deviations in behavior. Further studies are warranted to elucidate genomic findings suggestive of key mutations in this pathway.

The role of Hippo-Yes-associated protein (YAP) in human colorectal cancer (CRC) presents contradictory results. We examined the function of YAP in the early stages of CRC by quantitatively measuring the expression of phospho-YAPS127 (p-YAP) and five APC-related proteins in 145 sporadic adenomas from the Tennessee Colorectal Polyp Study, conducting APC sequencing for 114 adenomas, and analyzing YAP-correlated cancer pathways using gene expression data from 326 adenomas obtained from Gene Expression Omnibus. The p-YAP expression was significantly correlated with YAP expression (r = 0.53, P < .0001) and nuclear β-catenin (r = 0.26, P = .0018) in adenoma tissues. Both p-YAP and nuclear β-catenin were associated with APC mutations (P = .05). A strong association was observed between p-YAP overexpression and advanced adenoma odds (OR = 12.62, 95% CI = 4.57-34.86, P trend < .001), which persisted after adjusting for covariates and biomarkers (OR = 12.31, 95% CI = 3.78-40.10, P trend < .0001). P-YAP exhibited a sensitivity of 77.4% and specificity of 78.2% in defining advanced versus nonadvanced adenomas. Additionally, synergistic interaction was noted between p-YAP positivity and nuclear β-catenin on advanced adenomas (OR = 16.82, 95% CI = 4.41-64.08, P < .0001). YAP-correlated genes were significantly enriched in autophagy, unfolded protein response, and sirtuin pathways showing predominantly pro-tumorigenic alterations. Collectively, YAP plays an oncogenic role in interacting with Wnt as well as other cancer pathways within human sporadic adenomas. P-YAP could be a potential biomarker for human high-risk sporadic adenomas.

Autophagy is responsible for maintaining cellular balance and ensuring survival. Autophagy plays a crucial role in the development of diseases, particularly human cancers, with actions that can either promote survival or induce cell death. However, brain tumors contribute to high levels of both mortality and morbidity globally, with resistance to treatments being acquired due to genetic mutations and dysregulation of molecular mechanisms, among other factors. Hence, having knowledge of the role of molecular processes in the advancement of brain tumors is enlightening, and the current review specifically examines the role of autophagy. The discussion would focus on the molecular pathways that control autophagy in brain tumors, and its dual role as a tumor suppressor and a supporter of tumor survival. Autophagy can control the advancement of different types of brain tumors like glioblastoma, glioma, and ependymoma, demonstrating its potential for treatment. Autophagy mechanisms can influence metastasis and drug resistance in glioblastoma, and there is a complex interplay between autophagy and cellular responses to stress like hypoxia and starvation. Autophagy can inhibit the growth of brain tumors by promoting apoptosis. Hence, focusing on autophagy could offer fresh perspectives on creating successful treatments.

In a comprehensive study to decipher the multi-layered response to the chemotherapeutic agent temozolomide (TMZ), we analyzed 427 genomes and determined mutational patterns in a collection of ∼40 isogenic DNA repair-deficient human TK6 lymphoblast cell lines. We first demonstrate that the spontaneous mutational background is very similar to the aging-associated mutational signature SBS40 and mainly caused by polymerase zeta-mediated translesion synthesis (TLS). MSH2-/- mismatch repair (MMR) knockout in conjunction with additional repair deficiencies uncovers cryptic mutational patterns. We next report how distinct mutational signatures are induced by TMZ upon sequential inactivation of DNA repair pathways, mirroring the acquisition of chemotherapy resistance by glioblastomas. The most toxic adduct induced by TMZ, O6-meG, is directly repaired by the O6-methylguanine-DNA methyltransferase (MGMT). In MGMT-/- cells, MMR leads to cell death and limits mutagenesis. MMR deficiency results in TMZ resistance, allowing the accumulation of ∼105 C > T substitutions corresponding to signature SBS11. Under these conditions, N3-methyladenine (3-meA), processed by base excision repair (BER), limits cell survival. Without BER, 3-meA is read through via error-prone TLS, causing T > A substitutions but not affecting survival. Blocking BER after abasic site formation results in large deletions and TMZ hypersensitization. Our findings reveal potential vulnerabilities of TMZ-resistant tumors.

Mesothelioma is a fatal disease that has historically been associated with exposure to airborne asbestos. Because occupational asbestos exposures dropped dramatically in the late 1960s and early 1970s, far fewer cases of mesothelioma today are due to these fibers but, instead, are usually a result of the aging process or genetic predisposition. In May of 2022, a Morbidity and Mortality Weekly Report (MMWR) was issued by the Centers for Disease Control and Prevention (CDC) regarding malignant mesothelioma incidence in women from 1999 to 2020. While this MMWR alerted citizens to the continued presence of the disease, after reading this article one might have thought that the CDC was suggesting that the disease was increasing in women due to asbestos exposures (which it is not). In the present analysis, we investigate several factors related to the interpretation of epidemiological data for mesothelioma, including the role of asbestos as a risk factor over time. The authors conducted a review of the scientific community's understanding of mesothelioma incidence and asbestos exposures amongst women, as well as an investigation of the methods and references in the MMWR article. Although various articles have recently discussed the incidence of both peritoneal and pleural mesothelioma in women, it is fortunate that the age-adjusted rates for mesothelioma have remained flat (neither increased nor decreased significantly) in women for the past 50 years. Incredibly few women in the U. S. have had appreciable cumulative exposures to any type of asbestos (chrysotile, amosite, or crocidolite) in the workplace or from the ambient environment, especially since about 1965-1970. In this paper, we highlight six factors that should be considered when evaluating the incidence of mesothelioma amongst American women in the current era. Without sufficient consideration of these factors, improper conclusions have been drawn over the past several years.

Recent studies have reported increases in early-onset cancer cases (diagnosed under age 50) and call into question whether the increase is related to earlier diagnosis from other medical tests and reflected by decreasing tumor-size-at-diagnosis (apparent effects) or actual increases in underlying cancer risk (true effects), or both. The classic Multi-Stage Clonal Expansion (MSCE) model assumes cancer detection at the emergence of the first malignant cell, although later modifications have included lag-times or stochasticity in detection to more realistically represent tumor detection requiring a certain size threshold. Here, we introduce an approach to explicitly incorporate tumor-size-at-diagnosis in the MSCE framework and account for improvements in cancer detection over time to distinguish between apparent and true increases in early-onset cancer incidence. We demonstrate that our model is structurally identifiable and provides better parameter estimation than the classic model. Applying this model to colorectal, female breast, and thyroid cancers, we examine changes in cancer risk while accounting for detection improvements over time in three representative birth cohorts (1950-1954, 1965-1969, and 1980-1984). Our analyses suggest accelerated carcinogenic events and shorter mean sojourn times in more recent cohorts. We further use this model to examine the screening impact on the incidence of breast and colorectal cancers, both having established screening protocols. Our results align with well-documented differences in screening effects between these two cancers. These findings underscore the importance of accounting for tumor-size-at-diagnosis in cancer modeling and support true increases in early-onset cancer risk in recent years for breast, colorectal, and thyroid cancer.

Small GTPases Ras, Rac, and RhoA are crucial regulators of cellular functions. They also act in dysregulated cell proliferation and transformation. Multiple publications have focused on illuminating their roles and mechanisms, including in immune system pathologies. Their functions in neurology-related diseases, neurodegeneration and neurodevelopment, are also emerging, as well as their potential as pharmacological targets in both pathologies. Observations increasingly suggest that these pathologies may relate to activation (or suppression) of signaling by members of the Ras superfamily, especially Ras, Rho, and Rac isoforms, and components of their signaling pathways. Germline (or embryonic) mutations that they harbor are responsible for neurodevelopmental disorders, such as RASopathies, autism spectrum disorder, and dilated cardiomyopathy. In aging, they promote neurodegenerative diseases, with Rho GTPase featuring in their pharmacology, as in the case of Alzheimer's disease (AD). Significantly, drugs with observed anti-AD activity, particularly those involved in cardiovascular systems, are associated with the RhoA signaling, as well as cerebral vasculature in brain development and aging. This leads us to suggest that anti-AD drugs could inform neurodevelopmental disorders, including pediatric low-grade gliomas pharmacology. Neurodevelopmental disorders associated with RhoA, like autism, are also connected with vascular systems, thus could be targets of vascular system-connected drugs.

The main deterrent to long-term space travel is the risk of Radiation Exposure Induced Death (REID). The National Aeronautics and Space Administration (NASA) has adopted Permissible Exposure Levels (PELs) to limit the probability of REID to 3% for the risk of death due to radiation-induced carcinogenesis. The most significant contributor to current REID estimates for astronauts is the risk of lung cancer. Recently updated lung cancer estimates from Japan's atomic bomb survivors showed that the excess relative risk of lung cancer by age 70 is roughly fourfold higher in females compared to males. However, whether sex differences may impact the risk of lung cancer due to exposure to high charge and energy (HZE) radiation is not well studied. Thus, to evaluate the impact of sex differences on the risk of solid cancer development after HZE radiation exposure, we irradiated Rbfl/fl, Trp53fl/+ male and female mice infected with Adeno-Cre with various doses of 320 kVp X rays or 600 MeV/n 56Fe ions and monitored them for any radiation-induced malignancies. We conducted complete necropsy and histopathology of major organs on 183 male and 157 female mice after following them for 350 days postirradiation. We observed that lung adenomas/carcinomas and esthesioneuroblastomas (ENBs) were the most common primary malignancies in mice exposed to X rays and 56Fe ions, respectively. In addition, 1 Gy 56Fe-ion exposure compared to X-ray exposure led to a significantly increased incidence of lung adenomas/carcinomas (P = 0.02) and ENBs (P < 0.0001) in mice. However, we did not find a significantly higher incidence of any solid malignancies in female mice as compared to male mice, regardless of radiation quality. Furthermore, gene expression analysis of ENBs suggested a distinct gene expression pattern with similar hallmark pathways altered, such as MYC targets and MTORC1 signaling, in ENBs induced by X rays and 56Fe ions. Thus, our data revealed that 56Fe-ion exposure significantly accelerated the development of lung adenomas/carcinomas and ENBs compared to X rays, but the rate of solid malignancies was similar between male and female mice, regardless of radiation quality.

Cancers are typically fueled by sequential accumulation of driver mutations in a previously healthy cell. Some of these mutations, such as inactivation of the first copy of a tumor suppressor gene, can be neutral, and some, like those resulting in activation of oncogenes, may provide cells with a selective growth advantage. We study a multi-type branching process that starts with healthy tissue in homeostasis and models accumulation of neutral and advantageous mutations on the way to cancer. We provide results regarding the sizes of premalignant populations and the waiting times to the first cell with a particular combination of mutations, including the waiting time to malignancy. Finally, we apply our results to two specific biological settings: initiation of colorectal cancer and age incidence of chronic myeloid leukemia. Our model allows for any order of neutral and advantageous mutations and can be applied to other evolutionary settings.

Both mutation induction and clonal expansion of mutated cells cause cancer. The probability of cancer development depends on mutations, clonal growth rates, and carcinogenic mechanisms. A recent study showed cases of occupational cholangiocarcinomas that originate multifocally, with higher mutation burden levels than those in common cholangiocarcinomas. This study aimed to identify the effect of clonal expansion on and estimate the risk of occupational and common intrahepatic cholangiocarcinomas (ICCs) using a multistage model modified to include the effect of cell expansion at any carcinogenic stage.

The age-specific incidence of common ICC estimated from the Vital Statistics in Japan and the prognosis of ICC, and mutation frequencies of occupational and common ICC available from the previous report, were applied to a multistage model modified with cell proliferation effects. From the fittest model, the risk after exposure was estimated.

The required number of stages for carcinogenesis was estimated to be three based on the incidences and mutation frequencies of occupational and common ICCs. Based on this estimation, the predicted incidence curve under the model was similar to that estimated from the ICC mortality rate, except for older adults. The model indicated a minor effect of clonal expansion on the observed occupational ICC risk. It predicted a rapid decrease in ICC risk after the cessation of occupational exposure, although the time of clinical detection of cancer after the exposure was affected by latency. The model predicted an increase in cancer risk in older adults caused by cell expansion and common background mutations. However, the risk in older adults was overestimated in the case of common ICC; this divergence could influence occupational ICC cases.

Three-stage ICC carcinogenesis has been proposed. The high mutation burden levels caused by occupational exposure led to an immediate incidence of cancer. After a long period of relatively low cancer risk, an increased risk in older adults was also predicted.

Optimizing prevention and early detection of cancer requires understanding the number, types and timing of driver mutations. To quantify this, we exploited the elevated cancer incidence and mutation rates in germline BRCA1 and BRCA2 (gBRCA1/2) carriers. Using novel statistical models, we identify genomic deletions as the likely rate-limiting mutational processes, with 1-3 deletions required to initiate breast and ovarian tumors. gBRCA1/2-driven hereditary and sporadic tumors undergo convergent evolution to develop a similar set of driver deletions, and deletions explain the elevated cancer risk of gBRCA1/2-carriers. Orthogonal mutation timing analysis identifies deletions of chromosome 17 and 13q as early, recurrent events. Single-cell analyses confirmed deletion rate differences in gBRCA1/2 vs. non-carrier tumors as well as cells engineered to harbor gBRCA1/2. The centrality of deletion-associated chromosomal instability to tumorigenesis shapes interpretation of the somatic evolution of non-malignant tissue and guides strategies for precision prevention and early detection.

While it is recognised that most, if not all, multicellular organisms harbour neoplastic processes within their bodies, the timing of when these undesirable cell proliferations are most likely to occur and progress throughout the organism's lifetime remains only partially documented. Due to the different mechanisms implicated in tumourigenesis, it is highly unlikely that this probability remains constant at all times and stages of life. In this article, we summarise what is known about this variation, considering the roles of age, season and circadian rhythm. While most studies requiring that level of detail be done on humans, we also review available evidence in other animal species. For each of these timescales, we identify mechanisms or biological functions shaping the variation. When possible, we show that evolutionary processes likely played a role, either directly to regulate the cancer risk or indirectly through trade-offs. We find that neoplastic risk varies with age in a more complex way than predicted by early epidemiological models: rather than resulting from mutations alone, tumour development is dictated by tissue- and age-specific processes. Similarly, the seasonal cycle can be associated with risk variation in some species with life-history events such as sexual competition or mating being timed according to the season. Lastly, we show that the circadian cycle influences tumourigenesis in physiological, pathological and therapeutic contexts. We also highlight two biological functions at the core of these variations across our three timescales: immunity and metabolism. Finally, we show that our understanding of the entanglement between tumourigenic processes and biological cycles is constrained by the limited number of species for which we have extensive data. Improving our knowledge of the periods of vulnerability to the onset and/or progression of (malignant) tumours is a key issue that deserves further investigation, as it is key to successful cancer prevention strategies.

Hydrogels are promising candidates for the delivery of therapeutics in the treatment of human cancers. Regarding to the biocomaptiiblity, high drug and encapsulation efficacy and adjustable physico-chemical features, the hydrogels have been widely utilized for the delivery of chemotherapy drugs. Doxorubicin (DOX) is one of the most common chemotherapy drugs used in cancer therapy through impairing topoisomerase II function and increasing oxidative damage. However, the tumor cells have developed resistance into DOX-mediated cytotoxic impacts, requiring the delivery systems to increase internalization and anti-cancer activity of this drug. The hydrogels can deliver DOX in a sustained manner to maximize its anti-cancer activity, improving cancer elimination and reduction in side effects and drug resistance. The natural-based hydrogels such as chitosan, alginate and gelatin hydrogels have shown favourable biocompatibility and degradability in DOX delivery for tumor suppression. The hydrogels are able to co-deliver DOX with other drugs or genes to enhance drug sensitivity and mediate polychemotherapy, synergistically suppressing cancer progression. The incorporation of nanoparticles in the structure of hydrogels can improve the sustained release of DOX and enhancing intracellular internalization, accelerating DOX's cytotoxicity. Furthermore, the stimuli-responsive hydrogels including pH-, redox- and thermo-sensitive platforms are able to improve the specific release of DOX at the tumor site. The DOX-loaded hydrogels can be further employed in the clinic for the treatment of cancer patients and improving efficacy of chemotherapy.

Colorectal cancer (CRC) represents the second leading cause of cancer incidence and the third leading cause of cancer deaths worldwide. There is currently a lack of understanding of the onset of CRC, hindering the development of effective prevention strategies, early detection methods and the selection of appropriate therapies. This article outlines the key aspects of host genetics currently known about the origin and development of CRC. The organisation of the colonic crypts is described. It discusses how the transformation of a normal cell to a cancer cell occurs and how that malignant cell can populate an entire colonic crypt, promoting colorectal carcinogenesis. Current knowledge about the cell of origin of CRC is discussed, and the two morphological pathways that can give rise to CRC, the classical and alternative pathways, are presented. Due to the molecular heterogeneity of CRC, each of these pathways has been associated with different molecular mechanisms, including chromosomal and microsatellite genetic instability, as well as the CpG island methylator phenotype. Finally, different CRC classification systems are described based on genetic, epigenetic and transcriptomic alterations, allowing diagnosis and treatment personalisation.

Most computational methods for predicting driver mutations have been trained using positive samples, while negative samples are typically derived from statistical methods or putative samples. The representativeness of these negative samples in capturing the diversity of passenger mutations remains to be determined. To tackle these issues, we curated a balanced dataset comprising driver mutations sourced from the COSMIC database and high-quality passenger mutations obtained from the Cancer Passenger Mutation database. Subsequently, we encoded the distinctive features of these mutations. Utilizing feature correlation analysis, we developed a cancer driver missense mutation predictor called CDMPred employing feature selection through the ensemble learning technique XGBoost. The proposed CDMPred method, utilizing the top 10 features and XGBoost, achieved an area under the receiver operating characteristic curve (AUC) value of 0.83 and 0.80 on the training and independent test sets, respectively. Furthermore, CDMPred demonstrated superior performance compared to existing state-of-the-art methods for cancer-specific and general diseases, as measured by AUC and area under the precision-recall curve. Including high-quality passenger mutations in the training data proves advantageous for CDMPred's prediction performance. We anticipate that CDMPred will be a valuable tool for predicting cancer driver mutations, furthering our understanding of personalized therapy.

Pediatric low grade brain tumors and neurodevelopmental disorders share proteins, signaling pathways, and networks. They also share germline mutations and an impaired prenatal differentiation origin. They may differ in the timing of the events and proliferation. We suggest that their pivotal distinct, albeit partially overlapping, outcomes relate to the cell states, which depend on their spatial location, and timing of gene expression during brain development. These attributes are crucial as the brain develops sequentially, and single-cell spatial organization influences cell state, thus function. Our underlying premise is that the root cause in neurodevelopmental disorders and pediatric tumors is impaired prenatal differentiation. Data related to pediatric brain tumors, neurodevelopmental disorders, brain cell (sub)types, locations, and timing of expression in the developing brain are scant. However, emerging single cell technologies, including transcriptomic, spatial biology, spatial high-resolution imaging performed over the brain developmental time, could be transformational in deciphering brain pathologies thereby pharmacology.

Ferroptosis is a non-apoptotic form of cell death resulting from the iron-dependent accumulation of lipid peroxides. Colorectal cancer (CRC) cells accumulate high levels of intracellular iron and reactive oxygen species (ROS) and are thus particularly sensitive to ferroptosis. The compound (S)-RSL3 ([1S,3R]-RSL3) is a commonly used ferroptosis inducing compound that is currently characterized as a selective inhibitor of the selenocysteine containing enzyme (selenoprotein) Gluathione Peroxidase 4 (GPx4), an enzyme that utilizes glutathione to directly detoxify lipid peroxides. However, through chemical controls utilizing the (R) stereoisomer of RSL3 ([1R,3R]-RSL3) that does not bind GPx4, combined with inducible genetic knockdowns of GPx4 in CRC cell lines, we revealed that GPx4 dependency does not always align with (S)-RSL3 sensitivity, questioning the current characterization of GPx4 as the central regulator of ferroptosis. Utilizing affinity pull-down mass spectrometry with chemically modified (S)-RSL3 probes we discovered that the effects of (S)-RSL3 extend far beyond GPx4 inhibition, revealing that (S)-RSL3 is a broad and non-selective inhibitor of selenoproteins. To further investigate the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC, we employed additional chemical and genetic approaches. We found that the selenoprotein inhibitor auranofin, an FDA approved gold-salt, chemically induced oxidative cell death and ferroptosis in both in-vitro and in-vivo models of CRC. Consistent with these data, we found that AlkBH8, a tRNA-selenocysteine methyltransferase required for the translation of selenoproteins, is essential for the in-vitro growth and xenograft survival of CRC cell lines. In summary, these findings recharacterize the mechanism of action of the most commonly used ferroptosis inducing molecule, (S)-RSL3, and reveal that broad inhibition of selenoproteins is a promising novel therapeutic angle for the treatment of CRC.

Tissues achieve and maintain their sizes through active feedback, whereby cells collectively regulate proliferation and differentiation so as to facilitate homeostasis and the ability to respond to disturbances. One of the best understood feedback mechanisms-renewal control-achieves remarkable feats of robustness in determining and maintaining desired sizes. Yet in a variety of biologically relevant situations, we show that stochastic effects should cause rare but catastrophic failures of renewal control. We define the circumstances under which this occurs and raise the possibility such events account for important non-genetic steps in the development of cancer. We further suggest that the spontaneous stochastic reversal of these events could explain cases of cancer normalization or dormancy following treatment. Indeed, we show that the kinetics of post-treatment recurrence for many cancers are often better fit by a model of stochastic re-emergence due to loss of collective proliferative control, than by deterministic models of cancer relapse.

Kirsten Rat Sarcoma (KRAS) is the most commonly mutated oncogene in colorectal carcinoma (CRC). We have previously reported the interactions between microsatellite instability (MSI), DNA promoter methylation, and gene expression. In this study, we looked for associations between KRAS mutation, gene expression, and methylation that may help with precision medicine. Genome-wide gene expression and DNA methylation were done in paired CRC tumor and surrounding healthy tissues. The results suggested that (a) the magnitude of dysregulation of many major gene pathways in CRC was significantly greater in patients with the KRAS mutation, (b) the up- and down-regulation of these dysregulated gene pathways could be correlated with the corresponding hypo- and hyper-methylation, and (c) the up-regulation of CDKN2A was more pronounced in tumors with the KRAS mutation. A recent cell line study showed that there were higher CDKN2A levels in 5-FU-resistant CRC cells and that these could be down-regulated by Villosol. Our findings suggest the possibility of a better response to anti-CDKN2A therapy with Villosol in KRAS-mutant CRC. Also, the more marked up-regulation of genes in the proteasome pathway in CRC tissue, especially with the KRAS mutation and MSI, may suggest a potential role of a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) in selected CRC patients if necessary.

Cancer is a dynamic disease, and clonal heterogeneity plays a fundamental role in tumor development, progression, and resistance to therapies. Single-cell and spatial multimodal technologies can provide a high-resolution molecular map of underlying genomic, epigenomic, and transcriptomic alterations involved in inter- and intra-tumor heterogeneity and interactions with the microenvironment. In this review, we provide a perspective on factors driving cancer heterogeneity, tumor evolution, and clonal states. We briefly describe spatial transcriptomic technologies and summarize recent literature that sheds light on the dynamical interactions between tumor states, cell-to-cell communication, and remodeling local microenvironment.

Decades ago, mitogen-promoted signaling duration and strength were observed to be sensed by the cell and to be critical for its decisions: to proliferate or differentiate. Landmark publications established the importance of mitogen signaling not only in the G1 cell cycle phase but also through the S and the G2/M transition. Despite these early milestones, how mitogen signal duration and strength, short and strong or weaker and sustained, control cell fate has been largely unheeded. Here, we center on cardinal signaling-related questions, including (i) how fluctuating mitogenic signals are converted into cell proliferation-differentiation decisions and (ii) why extended duration of weak signaling is associated with differentiation, while bursts of strong and short induce proliferation but, if too strong and long, induce irreversible senescence. Our innovative broad outlook harnesses cell biology and protein conformational ensembles, helping us to define signaling strength, clarify cell cycle decisions, and thus cell fate.

Proteins are acknowledged as the phenotypical manifestation of the genotype, because protein-coding genes carry the information for the strings of amino acids that constitute the proteins. It is widely accepted that protein function depends on the corresponding "native" structure or folding achieved within the cell, and that native protein folding corresponds to the lowest free energy minimum for a given protein. However, protein folding within the cell is a non-deterministic dissipative process that from the same input may produce different outcomes, thus conformational heterogeneity of folded proteins is the rule and not the exception. Local changes in the intracellular environment promote variation in protein folding. Hence protein folding requires "supervision" by a host of chaperones and co-chaperones that help their client proteins to achieve the folding that is most stable according to the local environment. Such environmental influence on protein folding is continuously transduced with the help of the cellular stress responses (CSRs) and this may lead to changes in the rules of engagement between proteins, so that the corresponding protein interactome could be modified by the environment leading to an alternative cellular phenotype. This allows for a phenotypic plasticity useful for adapting to sudden and/or transient environmental changes at the cellular level. Starting from this perspective, hereunder we develop the argument that the presence of sustained cellular stress coupled to efficient CSRs may lead to the selection of an aberrant phenotype as the resulting adaptation of the cellular proteome (and the corresponding interactome) to such stressful conditions, and this can be a common epigenetic pathway to cancer.

The connection and causality between cancer and neurodevelopmental disorders have been puzzling. How can the same cellular pathways, proteins, and mutations lead to pathologies with vastly different clinical presentations? And why do individuals with neurodevelopmental disorders, such as autism and schizophrenia, face higher chances of cancer emerging throughout their lifetime? Our broad review emphasizes the multi-scale aspect of this type of reasoning. As these examples demonstrate, rather than focusing on a specific organ system or disease, we aim at the new understanding that can be gained. Within this framework, our review calls attention to computational strategies which can be powerful in discovering connections, causalities, predicting clinical outcomes, and are vital for drug discovery. Thus, rather than centering on the clinical features, we draw on the rapidly increasing data on the molecular level, including mutations, isoforms, three-dimensional structures, and expression levels of the respective disease-associated genes. Their integrated analysis, together with chromatin states, can delineate how, despite being connected, neurodevelopmental disorders and cancer differ, and how the same mutations can lead to different clinical symptoms. Here, we seek to uncover the emerging connection between cancer, including pediatric tumors, and neurodevelopmental disorders, and the tantalizing questions that this connection raises.

Small molecules are at the forefront of anticancer therapies. Successive treatments with single molecules incur drug resistance, calling for combination. Here, we explore the tough choices oncologists face - not just which drugs to use but also the best treatment plans, based on factors such as target proteins, pathways, and gene expression. We consider the reality of cancer's disruption of normal cellular processes, highlighting why it's crucial to understand the ins and outs of current treatment methods. The discussion on using combination drug therapies to target multiple pathways sheds light on a promising approach while also acknowledging the hurdles that come with it, such as dealing with pathway crosstalk. We review options and provide examples and the mechanistic basis, altogether providing the first comprehensive guide to combinatorial therapy selection.

Somatic mosaicism is a hallmark of malignancy that is also pervasively observed in human physiological aging, with clonal expansions of cells harboring mutations in recurrently mutated driver genes. Bulk sequencing of tissue microdissection captures mutation frequencies, but cannot distinguish which mutations co-occur in the same clones to reconstruct clonal architectures, nor phenotypically profile clonal populations to delineate how driver mutations impact cellular behavior. To address these challenges, we developed single-cell Genotype-to-Phenotype sequencing (scG2P) for high-throughput, highly-multiplexed, single-cell joint capture of recurrently mutated genomic regions and mRNA phenotypic markers in cells or nuclei isolated from solid tissues. We applied scG2P to aged esophagus samples from five individuals with high alcohol and tobacco exposure and observed a clonal landscape dominated by a large number of clones with a single driver event, but only rare clones with two driver mutations. NOTCH1 mutants dominate the clonal landscape and are linked to stunted epithelial differentiation, while TP53 mutants and double-driver mutants promote clonal expansion through both differentiation biases and increased cell cycling. Thus, joint single-cell highly multiplexed capture of somatic mutations and mRNA transcripts enables high resolution reconstruction of clonal architecture and associated phenotypes in solid tissue somatic mosaicism.

How tumors arise or the cause of precancerous lesions is a fundamental question in cancer biology. It is generally accepted that tumors originate from normal cells that undergo uncontrolled proliferation owing to genetic alterations. At the onset of adenoma formation, cancer driver mutations confer clonal growth advantage, enabling mutant cells to outcompete and eliminate the surrounding healthy cells. Hence, the development of precancerous lesions is not only attributed to the expansion of pre-malignant clones, but also relies on the relative fitness of mutated cells compared to the neighboring cells. Colorectal cancer (CRC) is an excellent model to investigate cancer origin as it follows a stereotypical process from mutant cell hyperplasia to adenoma formation and progression. Here, we review the evolving understanding of colonic tumor development, focusing on how cell intrinsic and extrinsic factors impact cell competition and the "clone war" between cancer-initiating cells and normal stem cells. We also discuss the promises and limitations of targeting cell competitiveness in cancer prevention and early intervention. The field of tumor initiation is currently in its infancy, elucidating the adenoma origin is crucial for designing effective prevention strategies and early treatments before cancer becomes incurable.

Despite the challenges posed by drug resistance and side effects, chemotherapy remains a pivotal strategy in cancer treatment. A key issue in this context is macroautophagy (commonly known as autophagy), a dysregulated cell death mechanism often observed during chemotherapy. Autophagy plays a cytoprotective role by maintaining cellular homeostasis and recycling organelles, and emerging evidence points to its significant role in promoting cancer progression. Cisplatin, a DNA-intercalating agent known for inducing cell death and cell cycle arrest, often encounters resistance in chemotherapy treatments. Recent studies have shown that autophagy can contribute to cisplatin resistance or insensitivity in tumor cells through various mechanisms. This resistance can be mediated by protective autophagy, which suppresses apoptosis. Additionally, autophagy-related changes in tumor cell metastasis, particularly the induction of Epithelial-Mesenchymal Transition (EMT), can also lead to cisplatin resistance. Nevertheless, pharmacological strategies targeting the regulation of autophagy and apoptosis offer promising avenues to enhance cisplatin sensitivity in cancer therapy. Notably, numerous non-coding RNAs have been identified as regulators of autophagy in the context of cisplatin chemotherapy. Thus, therapeutic targeting of autophagy or its associated pathways holds potential for restoring cisplatin sensitivity, highlighting an important direction for future clinical research.

Tumors are mostly characterized by genetic instability, as result of mutations in surveillance mechanisms, such as DNA damage checkpoint, DNA repair machinery and mitotic checkpoint. Defect in one or more of these mechanisms causes additive accumulation of mutations. Some of these mutations are drivers of transformation and are positively selected during the evolution of the cancer, giving a growth advantage on the cancer cells. If such mutations would result in mutated neoantigens, these could be actionable targets for cancer vaccines and/or adoptive cell therapies. However, the results of the present analysis show, for the first time, that the most prevalent mutations identified in human cancers do not express mutated neoantigens. The hypothesis is that this is the result of the selection operated by the immune system in the very early stages of tumor development. At that stage, the tumor cells characterized by mutations giving rise to highly antigenic non-self-mutated neoantigens would be efficiently targeted and eliminated. Consequently, the outgrowing tumor cells cannot be controlled by the immune system, with an ultimate growth advantage to form large tumors embedded in an immunosuppressive tumor microenvironment (TME). The outcome of such a negative selection operated by the immune system is that the development of off-the-shelf vaccines, based on shared mutated neoantigens, does not seem to be at hand. This finding represents the first demonstration of the key role of the immune system on shaping the tumor antigen presentation and the implication in the development of antitumor immunological strategies.

Tumor diseases become a huge problem when they embark on a path that advances to malignancy, such as the process of metastasis. Cancer metastasis has been thoroughly investigated from a biological perspective in the past, whereas it has still been less explored from a physical perspective. Until now, the intraluminal pathway of cancer metastasis has received the most attention, while the interaction of cancer cells with macrophages has received little attention. Apart from the biochemical characteristics, tumor treatments also rely on the tumor microenvironment, which is recognized to be immunosuppressive and, as has recently been found, mechanically stimulates cancer cells and thus alters their functions. The review article highlights the interaction of cancer cells with other cells in the vascular metastatic route and discusses the impact of this intercellular interplay on the mechanical characteristics and subsequently on the functionality of cancer cells. For instance, macrophages can guide cancer cells on their intravascular route of cancer metastasis, whereby they can help to circumvent the adverse conditions within blood or lymphatic vessels. Macrophages induce microchannel tunneling that can possibly avoid mechanical forces during extra- and intravasation and reduce the forces within the vascular lumen due to vascular flow. The review article highlights the vascular route of cancer metastasis and discusses the key players in this traditional route. Moreover, the effects of flows during the process of metastasis are presented, and the effects of the microenvironment, such as mechanical influences, are characterized. Finally, the increased knowledge of cancer metastasis opens up new perspectives for cancer treatment.

In January 2023, diagnosed with numerous metastases of lung cancer in my brain, I felt that I must accomplish a mission. If everything happens for a reason, my cancer, in particular, I must find out how metastatic cancer can be treated with curative intent. This is my mission now, and the reason I was ever born. In January 2023, I understood the meaning of life, of my life. I was born to write this article. In this article, I argue that monotherapy with targeted drugs, even when used in sequence, cannot cure metastatic cancer. However, preemptive combinations of targeted drugs may, in theory, cure incurable cancer. Also, I share insights on various topics, including rapamycin, an anti-aging drug that can delay but not prevent cancer, through my personal journey.

The effect of terahertz (THz) radiation has been studied in medicine. However, there is a lack of scientific information regarding its possible mutagenicity. Therefore, the present study aimed to assess the mutagenicity of 1.6 THz laser irradiation. The Ames test was conducted using five bacterial tester strains. The bacteria were subjected to (i) 1.6 THz laser irradiation at 3.8 mW/cm2 for 60 min using a tabletop THz pulse laser system, (ii) ultraviolet irradiation, (iii) treatment with positive control chemicals (positive control) or (iv) treatment with the solvent used in the positive control (negative control). After treatment, the bacterial suspensions were cultured on minimal glucose agar to determine the number of revertant colonies. In addition, the comet assay was performed using fibroblasts (V79) to assess possible DNA damage caused by the THz laser irradiation. The Ames test demonstrated that the THz laser irradiation did not increase the number of revertant colonies compared to that in the negative control group, whereas the ultraviolet irradiation and positive control treatment increased the number of revertant colonies. Thus, 1.6 THz laser irradiation is unlikely to be mutagenic. The comet assay additionally suggests that the THz laser irradiation unlikely induce cellular DNA damage.

SHP2 phosphatase promotes full activation of the RTK-dependent Ras/MAPK pathway. Its mutations can drive cancer and RASopathies, a group of neurodevelopmental disorders (NDDs). Here we ask how same residue mutations in SHP2 can lead to both cancer and NDD phenotypes, and whether we can predict what the outcome will be. We collected and analyzed mutation data from the literature and cancer databases and performed molecular dynamics simulations of SHP2 mutants. We show that both cancer and Noonan syndrome (NS, a RASopathy) mutations favor catalysis-prone conformations. As to cancer versus RASopathies, we demonstrate that cancer mutations are more likely to accelerate SHP2 activation than the NS mutations at the same genomic loci, in line with NMR data for K-Ras4B more aggressive mutations. The compiled experimental data and dynamic features of SHP2 mutants lead us to propose that different from strong oncogenic mutations, SHP2 activation by NS mutations is less likely to induce a transition of the ensemble from the SHP2 inactive state to the active state. Strong signaling promotes cell proliferation, a hallmark of cancer. Weak, or moderate signals are associated with differentiation. In embryonic neural cells, dysregulated differentiation is connected to NDDs. Our innovative work offers structural guidelines for identifying and correlating mutations with clinical outcomes, and an explanation for why bearers of RASopathy mutations may have a higher probability of cancer. Finally, we propose a drug strategy against SHP2 variants-promoting cancer and RASopathies.

The BRAF V600E mutation is frequently found in cancer. It activates the MAPK pathway and promotes cancer cell proliferation, making BRAF an excellent target for anti-cancer therapy. While BRAF-targeted therapy is highly effective for melanoma, it is often ineffective against other cancers harboring the BRAF mutation. In this study, we evaluate the effectiveness of a proteolysis targeting chimera (PROTAC), SJF-0628, in directing the degradation of mutated BRAF across a diverse panel of cancer cells and determine how these cells respond to the degradation. SJF-0628 treatment results in the degradation of BRAF V600E and a decrease in Mek activation in all cell lines tested, but the effects of the treatment on cell signaling and cell proliferation are cell-line-specific. First, BRAF degradation killed DU-4475 and Colo-205 cells via apoptosis but only partially inhibited the proliferation of other cancer cell lines. Second, SJF-0628 treatment resulted in co-degradation of MEK in Colo-205 cells but did not have the same effect in other cell lines. Finally, cell lines partially inhibited by BRAF degradation also contain other oncogenic drivers, making them multi-driver cancer cells. These results demonstrate the utility of a PROTAC to direct BRAF degradation and reveal that multi-driver oncogenesis renders some colorectal cancer cells resistant to BRAF-targeted treatment.