Publications list

(see below for a detailed presentation of selected publications)

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Selected publications

Epigenetic Fingerprints Link Early-Onset Colon and Rectal Cancer to Pesticide Exposure.

Silvana CE Maas, Iosune Baraibar, Odei Blanco-Irazuegui, Josep Tabernero, Elena Elez, Jose A. Seoane

The incidence of colorectal cancer (CRC) is rapidly rising in individuals younger than 50, particularly in high-income countries. This rise parallels shifts in lifestyle and environmental factors, collectively termed the exposome; however, whether these are causally linked to the development of early-onset CRC (EOCRC) has not been investigated. Due to limited exposome data in most cancer cohorts, we constructed weighted methylation risk scores (MRS) as proxies for exposome exposure to pinpoint specific risk factors associated with EOCRC. Our analysis confirms previously identified risk factors, such as educational attainment, diet, and smoking habits. Moreover, we identified the exposure to the herbicide picloram as a novel risk factor (Padj. = 0.00049), a result we replicated in a meta-analysis comprising six CRC cohorts (P = 0.021), comparing EOCRC cases with patients diagnosed aged ≥70. Subsequently, we employed population-based data from 81 U.S. counties over 20 years and validated the association between picloram usage and EOCRC incidence (P = 2.87×10-3). These findings highlight the critical role of the exposome in EOCRC risk, underscoring the urgency for targeted personal and policy-level interventions.

Exposomal determinants of non-genetic plasticity in tumor initiation

Davide Carra, Silvana CE Maas, Jose A. Seoane, Direna Alonso-Curbelo

The classical view of cancer as a genetically driven disease has been challenged by recent findings of oncogenic mutations in phenotypically healthy tissues, refocusing attention on non-genetic mechanisms of tumor initiation. In this context, gene–environment interactions take the stage, with recent studies showing how they unleash and redirect cellular and tissue plasticity towards protumorigenic states in response to the exposome, the ensemble of environmental factors impinging on tissue homeostasis. We conceptualize tumor-initiating plasticity as a phenotype-transforming force acting at three levels: cell-intrinsic, focusing on mutant epithelial cells’ responses to environmental variation; reprogramming of non-neoplastic cells of the host, leading to protumor micro- and macroenvironments; and microbiome ecosystem dynamics. This perspective highlights cell, tissue, and organismal plasticity mechanisms underlying tumor initiation that are shaped by the exposome, and how their functional investigation may provide new opportunities to prevent, detect, and intercept cancer-promoting plasticity.

Multimodal data integration in early-stage breast cancer

Arnau Llinas-Bertran, Maria Butjosa-Espína, Vittoria Barberib, Jose A. Seoane

The use of biomarkers in breast cancer has significantly improved patient outcomes through targeted therapies, such as hormone therapy anti-Her2 therapy and CDK4/6 or PARP inhibitors. However, existing knowledge does not fully encompass the diverse nature of breast cancer, particularly in triple-negative tumors. The integration of multi-omics and multimodal data has the potential to provide new insights into biological processes, to improve breast cancer patient stratification, enhance prognosis and response prediction, and identify new biomarkers. This review presents a comprehensive overview of the state-of-the-art multimodal (including molecular and image) data integration algorithms developed and with applicability to breast cancer stratification, prognosis, or biomarker identification. We examined the primary challenges and opportunities of these multimodal data integration algorithms, including their advantages, limitations, and critical considerations for future research. We aimed to describe models that are not only academically and preclinically relevant, but also applicable to clinical settings.

Chromatin regulators mediate anthracycline sensitivity in breast cancer

Jose A. Seoane, Jacob G. Kirkland, Jennifer L. Caswell-Jin, Gerald R. Crabtree, Christina Curtis

Anthracyclines are a highly effective component of curative breast cancer chemotherapy but are associated with substantial morbidity1,2. Because anthracyclines work in part by inhibiting topoisomerase-II (TOP2) on accessible DNA3,4, we hypothesized that chromatin regulatory genes (CRGs) that mediate DNA accessibility might predict anthracycline response. We studied the role of CRGs in anthracycline sensitivity in breast cancer through integrative analysis of patient and cell line data. We identified a consensus set of 38 CRGs associated with anthracycline response across ten cell line datasets. By evaluating the interaction between expression and treatment in predicting survival in a metacohort of 1006 patients with early-stage breast cancer, we identified 54 CRGs whose expression levels dictate anthracycline benefit across the clinical subgroups; of these CRGs, 12 overlapped with those identified in vitro. CRGs that promote DNA accessibility, including Trithorax complex members, were associated with anthracycline sensitivity when highly expressed, whereas CRGs that reduce accessibility, such as Polycomb complex proteins, were associated with decreased anthracycline sensitivity. We show that KDM4B modulates TOP2 accessibility to chromatin, elucidating a mechanism of TOP2 inhibitor sensitivity. These findings indicate that CRGs mediate anthracycline benefit by altering DNA accessibility, with implications for the stratification of patients with breast cancer and treatment decision making.