Biology subjects

Fodde, R.

Publications and source records attributed to Fodde, R..

8 recordsLinked to original sources

bioRxiv2026

Inflammation-driven reprogramming of goblet cells underlies the onset of serrated adenomas in colon cancer

In the context of inflammation, fully committed and post-mitotic cell lineages can initiate intestinal tumorigenesis in the mouse through dedifferentiation and acquisition of revival stem cell (RSC) features1,2. Likewise, by means of machine-learning analysis of whole-genome mutation spectra, the secretory goblet cell was predicted as the most frequent cell-of-origin (COO) of colon cancer in inflammatory bowel disease (IBD) patients2. Of note, even among sporadic (non-IBD) colon cancer patients, goblet cells were predicted as the most common differentiated COO of cancer in the colonic epithelium2, suggestive of the main role played by diet-induced inflammation in the onset of a large proportion of malignancies of the large bowel. However, how goblet cells respond to inflammation and reprogram their identity to become potential tumor-initiating cells remains unclear. Here, by taking advantage of publicly available single-cell RNAseq data from colonic tissues of ulcerative colitis (UC) patients3, we have characterized the inflammation-driven reprogramming of goblet cells. By means of an RNA velocity-based computational approach, we show that the mucus-producing goblet cells acquire an aberrant proliferative state earmarked by MUC5AC+ expression. Trajectory analysis of serrated adenoma cells4 reveal aberrant goblet cells as an intermediate state in the transition to revival stem cells, notably more common in BRAF-mutant cases. In support of these findings, COO predictions using whole-genome mutation spectra from a cohort of sporadic colon cancers5 connect tumors with a predicted goblet origin to BRAF mutations and reveal transcriptional remnants of the aberrant goblet cell state.

Cancer Biology↗

bioRxiv2026

Western diet suppresses canonical intestinal stem cells and reprograms c-Kit+ reserve stem cells via proinflammatory dysbiosis

While colorectal cancer (CRC) is thought to originate primarily from resident stem cells, diet heavily influences intestinal stem cell homeostasis and disease onset. In this study, we demonstrate that a Western-style diet (WSD) alters intestinal homeostasis by uncoupling canonical stemness from tumorigenesis. WSD exposure suppresses canonical Lgr5 stem cells while activating an alternative pool of facultative c-Kit secretory cells. Although these reprogrammed stem-like cells exhibit genotoxic stress, they remain proliferative under prolonged dietary exposure, suggesting increased susceptibility to tumor-initiating mutations. We identify diet-induced microbial shifts and the expansion of enterotoxigenic Bacteroides fragilis (ETBF) as the upstream driver. ETBF and its toxin fragilysin autonomously trigger multipotency in c-Kit+ cells through Wnt/{beta}-catenin and YAP signaling. Importantly, these alterations are fully reversible upon dietary intervention. Together, our results highlight a targetable dietary-microbial axis that shapes epithelial stemness and underscores the role of facultative stem cells in diet-induced CRC onset.

cell biology↗

bioRxiv2025

Integrin-TGFβ axis induces partial EMT in basal-like cells to lead collective invasion

Collective invasion is the predominant mode of cancer cell dissemination in breast cancer and represents the initial step of metastatic spread. Basal-like leader cells drive this process by maintaining cell-cell junctions with the follower cells while extending actin-rich protrusions and remodeling the collagen I-rich peritumoral stroma. These features resemble those of individually-invading cells following epithelial-to-mesenchymal transition (EMT). However, how leader cells acquire these traits while preserving cohesion within the collective remains unclear. Here, we identify a collagen I-responsive subset of basal-like cells that coexpress cytoskeletal, extracellular matrix (ECM)-remodeling, and epithelial junction genes. We show that integrin 2 (Itg2) links collagen I engagement to mesenchymal reprogramming by inducing inhibin beta A (INHBA) expression and activating tumor growth factor {beta} (TGF{beta}) signaling. This, in turn, upregulates vimentin while preserving epithelial junction gene expression. In parallel, Itg2 promotes ECM degradation through a TGF{beta}-independent mechanism. This study identifies Itg2-TGF{beta} axis as a key regulator of partial EMT and leader cell function, highlighting it as a potential therapeutic target in aggressive breast cancers.

cell biology↗

bioRxiv2024

A tug-of-war between the NuRD and SWI/SNF chromatin remodelers regulates the coordinated activation of Epithelial-Mesenchymal Transition and inflammation in oral cancer.

Phenotypic plasticity and inflammation, two well-established hallmarks of cancer, play key roles in local invasion and distant metastasis by enabling rapid adaptation of tumor cells to dynamic micro- environmental changes. Here, we show that in oral squamous carcinoma cell carcinoma (OSCC), the competition between the NuRD and SWI/SNF chromatin remodeling complexes plays a pivotal role in regulating both epithelial-mesenchymal plasticity (EMP) and inflammation. By perturbing these complexes, we demonstrate their opposing downstream effects on inflammatory pathways and EMP regulation. In particular, downregulation of the BRG1-specific SWI/SNF complex deregulates key inflammatory genes such as TNF- and IL6 in opposite ways when compared with loss of CDK2AP1, a key member of the NuRD complex. We show that CDK2AP1 genetic ablation triggers a pro-inflammatory secretome encompassing several chemo- and cytokines thus promoting the recruitment of monocytes into the tumor microenvironment (TME). Furthermore, CDK2AP1 deletion stimulates their differentiation into M2-like macrophages, as also validated on tumor microarrays from OSCC patient- derived tumor samples. Further analysis of the inverse correlation between CDK2AP1 expression and TME immune infiltration revealed specific downstream effects on CD68+ macrophage abundance and localization. Our study sheds light on the role of chromatin remodeling complexes in OSCC locoregional invasion and points at the potential of CDK2AP1 and other members of the NuRD and SWI/SNF chromatin remodeling complexes as prognostic markers and therapeutic targets.

cancer biology↗

bioRxiv2023

The origin of intestinal cancer in the context of inflammation

According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, was shown to suppress intestinal stemness. Here, we employed Paneth cells (PCs) as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation. Upon inflammation, PC-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in inflammatory bowel disease (IBD) patients but also of a larger fraction of sporadic colon cancers. The latter is likely due to the inflammatory consequences of Western-style dietary habits, the major colon cancer risk factor. Computational methods designed to predict the cell-of-origin of cancer confirmed that, in a substantial fraction of sporadic colon cancers the cells-of-origin are secretory lineages and not stem cells. One-Sentence SummarySecretory cell lineages trigger tumor formation in the context of the major etiologic colon cancer risk factors.

cancer biology↗

bioRxiv2022

Alternative splicing downstream of EMT enhances phenotypic plasticity and malignant behavior in colon cancer

Phenotypic plasticity allows carcinoma cells to transiently acquire the quasi-mesenchymal features necessary to detach from the primary mass and proceed along the invasion-metastasis cascade. A broad spectrum of epigenetic mechanisms is likely to cause the epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) transitions necessary to allow local dissemination and distant metastasis. Here, we report on the role played by alternative splicing (AS) in eliciting phenotypic plasticity in colon cancer. By taking advantage of the identification of a subpopulation of quasi-mesenchymal and highly metastatic EpCAMlo colon cancer cells, we here show that the differential expression of ESRP1 and other RNA-binding proteins (RBPs) downstream of the EMT master regulator ZEB1, alters the AS pattern of a broad spectrum of targets including CD44 and NUMB, thus resulting in the generation of specific isoforms functionally associated with increased invasion and metastasis. Additional functional and validation studies indicate that both the newly identified RBPs and the CD44s and NUMB2/4 splicing isoforms promote local invasion and distant metastasis and are associated with poor survival. The systematic elucidation of the spectrum of EMT-related RBPs and AS targets in colon cancer and in other malignancies, apart from the insights in the mechanisms underlying phenotypic plasticity, will lead to the identification of novel and tumor-specific therapeutic targets.

cancer biology↗

bioRxiv2020

APC mutant cells exploit compensatory chromosome alterations to restore tumour cell fitness

Cancer cells tolerate copy number alterations (CNAs) of genomic regions that are lethal to non-cancer cells. Certain CNAs are preferentially associated with specific cancer types and lineages, but the mechanisms underlying the emergence and selection of specific CNAs remain unclear. Adenomatous polyposis coli (APC) mutations induce mitotic errors, but their impact on tumor evolution remains elusive. We investigated APC function in cultured cells and tumors and found that its loss led to {beta}-catenin accumulation at centrosomes, suppressing its maturation through inhibition of key centrosome regulators, including Aurora kinase A (AURKA) that promotes tumor growth. These defects collectively reduced cellular fitness, leading to impaired mitotic fidelity and delayed cell cycle progression. However, in APC-mutant tumors, AURKA activity was maintained, at least in part, through the amplification of chromosomes harboring AURKA and its activator genes, yet this alone was insufficient to fully restore proliferation: aberrant chromosomal reorganization also emerged and contributed to the adaptive fitness of APC-mutant cells. Such a process of adaptive CNA selection provides a framework for understanding how specific CNAs are selected to counteract disadvantages imposed by genetic alterations during tumor progression, providing one key insight into how specific CNAs are selected in this context.

cell biology↗

bioRxiv2020

Phenotypic plasticity and partial EMT underlie local invasion and distant metastasis in colon cancer

Phenotypic plasticity represents the most relevant hallmark of the carcinoma cell as it bestows it with the capacity of transiently altering its morphologic and functional features while en route to the metastatic site. However, the study of phenotypic plasticity is hindered by the rarity of these events within primary lesions and by the lack of experimental models. Here, we identified a subpopulation of phenotypic plastic colon cancer cells: EpCAMlo cells are motile, invasive, chemo-resistant, and highly metastatic. EpCAMlo bulk and single-cell RNAseq analysis indicated 1. enhanced Wnt/{beta}-catenin signaling, 2. a broad spectrum of degrees of EMT activation including hybrid E/M states (partial EMT) with highly plastic features, and 3. high correlation with the CMS4 subtype, accounting for colon cancer cases with poor prognosis and a pronounced stromal component. Of note, a signature of genes specifically expressed in EpCAMlo cancer cells is highly predictive of overall survival in tumors other than CMS4, thus highlighting the relevance of quasi-mesenchymal tumor cells across the spectrum of colon cancers. Enhanced Wnt and the downstream EMT activation represent key events in eliciting phenotypic plasticity along the invasive front of primary colon carcinomas. Distinct sets of epithelial and mesenchymal genes define transcriptional trajectories through which state transitions arise. pEMT cells, often earmarked by the extracellular matrix glycoprotein SPARC together with nuclear ZEB1 and {beta}-catenin along the invasive front of primary colon carcinomas, are predicted to represent the origin of these (de)differentiation routes through biologically-distinct cellular states, and to underlie the phenotypic plasticity of colon cancer cells.

cancer biology↗