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Claudin-low breast cancers are aggressive tumors defined by the low expression of key components of cellular junctions, associated with mesenchymal and stemness features. Although they are generally considered as the most primitive breast malignancies, their histogenesis remains elusive. Here we show that this molecular subtype of breast cancers exhibits a significant diversity, comprising three main subgroups that emerge from unique evolutionary processes. Genetic, gene methylation and gene expression analyses reveal that two of the subgroups relate, respectively, to luminal breast cancers and basal-like breast cancers through the activation of an EMT process over the course of tumor progression. The third subgroup is closely related to normal human mammary stem cells. This unique subgroup of breast cancers shows a paucity of genomic aberrations and a low frequency of TP53 mutations, supporting the emerging notion that the intrinsic properties of the cell-of-origin constitute a major determinant of the genetic history of tumorigenesis. Claudin-low tumors are a rare aggressive subtype of breast cancers. In this study, the authors use a multiomics approach to demonstrate that these tumors are heterogeneous and comprise three main subgroups that emerge from different evolutionary processes.

Small intestinal neuroendocrine tumors (siNETs) are rare bowel tumors arising from malignant enteroendocrine cells, which normally regulate digestion throughout the intestine. Though infrequent, their incidence is rising through better diagnosis, fostering research into their origin and treatment. To date, siNETs are considered to be a single entity and are clinically treated as such. Here, by performing a multi-omics analysis of siNETs, we unveil four distinct molecular groups with strong clinical relevance and provide a resource to study their origin and clinical features. Transcriptomic, genetic and DNA methylation profiles identify two groups linked to distinct enteroendocrine differentiation patterns, another with a strong immune phenotype, and the last with mesenchymal properties. This latter subtype displays the worst prognosis and resistance to treatments in line with infiltration of cancer-associated fibroblasts. These data provide insights into the origin and diversity of these rare diseases, in the hope of improving clinical research into their management. Small intestinal neuroendocrine tumours (siNETs) are rare bowel tumors generally considered to be a single entity. Here, the authors perform a multiomics analysis of siNETs and reveal four distinct molecular groups with clinical relevance, including groups linked to differentiation patterns, immunity, and mesenchymal properties.

Targeted therapies with MAPK inhibitors (MAPKi) are faced with severe problems of resistance in BRAF ‐mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAF V 600 ‐mutated cell lines and tumors. ZEB1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment. ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting a reversible transition toward a MITF low /p75 high stem‐like and tumorigenic phenotype. ZEB1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo , sensitizes naive melanoma cells to MAPKi, and induces cell death in resistant cells. Overall, our results demonstrate that ZEB1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPKi. Synopsis The EMT‐inducing transcription factor ZEB1 is found to be a crucial determinant of melanoma phenotype switching, tumorigenicity, and resistance to MAPKi by favoring rapid drug adaptation. High ZEB1 and low MITF expression levels are associated with inherent resistance to MAPK inhibitors (MAPKi) in BRAF V 600 ‐mutated cell lines and tumors. ZEB1 expression is increased in melanoma cell lines with acquired resistance to MAPKi and in biopsies from patients relapsing while under treatment. ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting the reversible conversion of a MITF high /p75 low differentiated state into a MITF low /p75 high stem‐like and tumorigenic state. ZEB1 inhibition sensitizes naive melanoma cells to MAPKi and induces cell death in resistant melanoma cells. Graphical Abstract The EMT‐inducing transcription factor ZEB1 is found to be a crucial determinant of melanoma phenotype switching, tumorigenicity, and resistance to MAPKi by favoring rapid drug adaptation.

The conventional diagnostic and prognostic biomarkers (i.e. Clark Level (CL), Breslow Index (BI) or immunohistochemical markers [2]) seem insufficient to distinguish precisely primary epidermis-limited neoplasms from aggressive or advanced/metastatic melanomas, and to assess the outcome for individual patients. [...]additional relevant biomarkers are needed to predict the individual risk of metastasis and monitor disease progression. [...]we identified several Tspan8 transcriptional regulators whose deregulation leads to Tspan8 expression [3, 5, 6], which could help to design new therapeutic strategies targeting Tspan8. Tspan8 protein expression in human primary melanomas was correlated with a higher propensity to give rise to distant metastases and an increased risk of death To evaluate the impact of Tspan8 expression at the protein level, we performed Tspan8 immunohistochemical staining analysis in a cohort of 100 primary melanoma samples: 73% of primary melanomas were positive for Tspan8 protein expression (sup. Tspan8 protein seemed more frequently expressed in the thinnest melanomas from patients dead during the 5-year period after diagnosis (92.3% of samples). [...]the thinnest primary melanomas seemed to express the highest levels of Tspan8 protein (immunointensity score 4 exclusively in < 1 mm samples), especially in patients’ dead 5-years after diagnosis (60% of immunointensity scores 3–4; Fig. 2c).

Cell plasticity sustains intra-tumor heterogeneity and treatment resistance in melanoma. Deciphering the transcriptional mechanisms governing reversible phenotypic transitions between proliferative/differentiated and invasive/stem-like states is required. Expression of the ZEB1 transcription factor is frequently activated in melanoma, where it fosters adaptive resistance to targeted therapies. Here, we performed a genome-wide characterization of ZEB1 transcriptional targets, by combining ChIP-sequencing and RNA-sequencing, upon phenotype switching in melanoma models. We identified and validated ZEB1 binding peaks in the promoter of key lineage-specific genes crucial for melanoma cell identity. Mechanistically, ZEB1 negatively regulates SOX10-MITF dependent proliferative/melanocytic programs and positively regulates AP-1 driven invasive and stem-like programs. Comparative analyses with breast carcinoma cells revealed lineage-specific ZEB1 binding, leading to the design of a more reliable melanoma-specific ZEB1 regulon. We then developed single-cell spatial multiplexed analyses to characterize melanoma cell states intra-tumoral heterogeneity in human melanoma samples. Combined with scRNA-Seq analyses, our findings confirmed increased ZEB1 expression in Neural-Crest-like cells and mesenchymal cells, underscoring its significance in vivo in both populations. Overall, our results define ZEB1 as a major transcriptional regulator of cell states transitions and provide a better understanding of lineage-specific transcriptional programs sustaining intra-tumor heterogeneity in melanoma.

Breast cancer cells frequently acquire mutations in faithful DNA repair genes, as exemplified by BRCA-deficiency. Moreover, overexpression of an inaccurate DNA repair pathway may also be at the origin of the genetic instability arising during the course of cancer progression. The specific gain in expression of POLQ , encoding the error-prone DNA polymerase Theta (POLθ) involved in theta-mediated end joining (TMEJ), is associated with a characteristic mutational signature. To gain insight into the mechanistic regulation of POLQ expression, this review briefly presents recent findings on the regulation of POLQ in the claudin-low breast tumor subtype, specifically expressing transcription factors involved in epithelial-to-mesenchymal transition (EMT) such as ZEB1 and displaying a paucity in genomic abnormality.

Due to its high proclivity to metastasize, and despite the recent development of targeted and immune therapy strategies, melanoma is still the deadliest form of skin cancer. Therefore, understanding the molecular mechanisms underlying melanoma invasion remains crucial. We previously characterized Tspan8 for its ability to prompt melanoma cell detachment from their microenvironment and trigger melanoma cell invasiveness, but the signaling events by which Tspan8 regulates the invasion process still remain unknown. Here, we demonstrated that β-catenin stabilization is a molecular signal subsequent to the onset of Tspan8 expression, and that, in turn, β-catenin triggers the direct transcriptional activation of Tspan8 expression, leading to melanoma invasion. Moreover, we showed that β-catenin activation systematically correlates with a high expression of Tspan8 protein in melanoma lesions from transgenic Nras; bcat* mice, as well as in deep penetrating naevi, a type of human pre-melanoma neoplasm characterized by a combined activation of β-catenin and MAP kinase signaling. Overall, our data suggest that β-catenin and Tspan8 are part of a positive feedback loop, which sustains a high Tspan8 expression level, conferring to melanoma cells the invasive properties required for tumor progression and dissemination.

Pancreatic ductal adenocarcinoma (PDAC) is one of the solid tumors with the poorest prognosis. The stroma of this tumor is abundant and composed of extracellular matrix and stromal cells (including cancer-associated fibroblasts and immune cells). Nerve fibers invading this stroma represent a hallmark of PDAC, involved in neural remodeling, which participates in neuropathic pain, cancer cell dissemination and tumor relapse after surgery. Pancreatic cancer-associated neural remodeling is regulated through functional interplays mediated by physical and molecular interactions between cancer cells, nerve cells and surrounding Schwann cells, and other stromal cells. In the present study, we show that Schwann cells (glial cells supporting peripheral neurons) can enhance aggressiveness (migration, invasion, tumorigenicity) of pancreatic cancer cells in a transforming growth factor beta (TGFβ)-dependent manner. Indeed, we reveal that conditioned medium from Schwann cells contains high amounts of TGFβ able to activate the TGFβ-SMAD signaling pathway in cancer cells. We also observed in human PDAC samples that high levels of TGFβ signaling activation were positively correlated with perineural invasion. Secretome analyses by mass spectrometry of Schwann cells and pancreatic cancer cells cultured alone or in combination highlighted the central role of TGFβ in neuro-epithelial interactions, as illustrated by proteomic signatures related to cell adhesion and motility. Altogether, these results demonstrate that Schwann cells are a meaningful source of TGFβ in PDAC, which plays a crucial role in the acquisition of aggressive properties by pancreatic cancer cells.

Due to its high proclivity to metastasize, and despite the recent development of targeted and immune therapy strategies, melanoma is still the deadliest form of skin cancer. Therefore, understanding the molecular mechanisms underlying melanoma invasion remains crucial. We previously characterized Tspan8 for its ability to prompt melanoma cell detachment from their microenvironment and trigger melanoma cell invasiveness, but the signaling events by which Tspan8 regulates the invasion process still remain unknown. Here, we demonstrated that [beta]-catenin stabilization is a molecular signal subsequent to the onset of Tspan8 expression, and that, in turn, [beta]-catenin triggers the direct transcriptional activation of Tspan8 expression, leading to melanoma invasion. Moreover, we showed that [beta]-catenin activation systematically correlates with a high expression of Tspan8 protein in melanoma lesions from transgenic Nras; bcat* mice, as well as in deep penetrating naevi, a type of human pre-melanoma neoplasm characterized by a combined activation of [beta]-catenin and MAP kinase signaling. Overall, our data suggest that [beta]-catenin and Tspan8 are part of a positive feedback loop, which sustains a high Tspan8 expression level, conferring to melanoma cells the invasive properties required for tumor progression and dissemination.

Peripheral T cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcomes. The T cell receptor (TCR) is emerging as a key driver of T lymphocyte transformation. However, the role of chronic TCR activation in lymphomagenesis and in lymphoma cell survival is still poorly understood. Using a mouse model, we report that chronic TCR stimulation drove T cell lymphomagenesis, whereas TCR signaling did not contribute to PTCL survival. The combination of kinome, transcriptome, and epigenome analyses of mouse PTCLs revealed a NK cell-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and SYK. Activating NKRs were functional in PTCLs and dependent on SYK activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKRs and downstream SYK/mTOR activity for their survival. We studied a large collection of human primary samples and identified several PTCLs recapitulating the phenotype described in this model by their expression of SYK and the NKR, suggesting a similar mechanism of lymphomagenesis and establishing a rationale for clinical studies targeting such molecules.