Genomic and microenvironmental heterogeneity shaping epithelial-to-mesenchymal trajectories in cancer

Abstract

The epithelial to mesenchymal transition (EMT) is a key cellular process underlying cancer progression, with multiple intermediate states whose molecular hallmarks remain poorly characterised. To fill this gap, we present a method to robustly evaluate EMT transformation in individual tumours based on transcriptomic signals. We apply this approach to explore EMT trajectories in 7180 tumours of epithelial origin and identify three macro-states with prognostic and therapeutic value, attributable to epithelial, hybrid E/M and mesenchymal phenotypes. We show that the hybrid state is relatively stable and linked with increased aneuploidy. We further employ spatial transcriptomics and single cell datasets to explore the spatial heterogeneity of EMT transformation and distinct interaction patterns with cytotoxic, NK cells and fibroblasts in the tumour microenvironment. Additionally, we provide a catalogue of genomic events underlying distinct evolutionary constraints on EMT transformation. This study sheds light on the aetiology of distinct stages along the EMT trajectory, and highlights broader genomic and environmental hallmarks shaping the mesenchymal transformation of primary tumours.

SpottedPy quantifies relationships between spatial transcriptomic hotspots and uncovers new environmental cues of epithelial-mesenchymal plasticity in cancer

“…We uncovered heterogeneous relationships across breast tissue slides with other key immune cells such as NK cells, NKT cells and T cells, highlighting the multifaceted interplay between these components. T-cells have been shown to induce EMT in breast cancer 67,68 , and this relationship has further been highlighted in bulk transcriptomics 69 and smaller scale spatial transcriptomic analyses 34,70 however there is also evidence showing the exclusion of these cells, linked to the relationship between EMT, macrophages and CAFs promoting an immune suppressed environment 64,51,71 . Indeed, our findings uncover notable associations between EMT hotspots and immune suppression, alongside signatures indicative of a response to checkpoint therapy, building upon evidence that EMT may offer crucial insights for existing strategies in immunotherapy 72,11 .…”

Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer

“…Complementarily, we here show that JUNB/AP1 acts as a counterpart to promote a favorable CLA phenotypic identity in PDAC. Of note, JUNB/AP1-mediated transcriptional programs can also confer tumor-promoting functions in other cancer types [39][40][41] ; JUN/AP1 TFs are highly context dependent and may co-operate for target gene transcription [41][42][43] or oppose one another 44 Altogether, this string of insights provides a potential mechanistic foundation for several recent studies that showed a high degree of heterogeneity in the neoplastic and stromal immune compartments in human PDAC, including hybrid/intermediate/coexpressor CLA/BL subtype states that exist in naive and therapy-treated PDAC tumors [10][11][12][13][14][15][16]20,36,37 . We propose that extrinsic regional TNF-α plays an essential role in destabilizing CLA neoplastic cell identity by promoting BL cJUN/AP1-mediated transcriptional programs.…”

“…Here, we investigated the role of neoplastic AP1-mediated epigenetic and transcriptional programs in shaping the local inflammatory TiME, which in turn is critical for intratumoral subtype plasticity and PDAC aggressiveness [10][11][12][13][14][15]20,36,37 . We report that AP1 transcription factors (JUNB/AP1 vs. cJUN/AP1) hold a dichotomous role in maintaining both the plasticity and stability of CLA and BL neoplastic cells via intrinsic epigenetic and transcriptional regulation of lineage gene expression as well as extrinsic inflammatory processes.…”

“…However, it has become clear that the CLA and BL subtypes are not discrete states of individual PDAC tumors, but rather co-exist and contribute to significant intratumoral heterogeneity that is poorly understood. Multi-scale transcriptomic and imaging-based profiling has revealed a widespread co-existence of CLA and BL subtypes within PDAC patient tumors, as well as hybrid/co-expressor states that are implicated as transition mechanism between the subtype extremes [10][11][12][13][14][15] , emphasizing the complex tumor cell plasticity. Moreover, the extent of subtype co-existence increases in advanced disease, especially in metastatic samples 13,16,17 .…”

Phenomics demonstrates cytokines additive induction of epithelial to mesenchymal transition

“…EMT can be tracked with transcriptomic methods, which are costly and don't integrate all parameters, including the morphological aspect or single-cell variation. [13] Each cell, even in homogenous condition, can be modified or modify itself from its population. [14] Single cell variation is a necessity in organism, but also a major issue when it comes to treatment, especially in highly heterogeneous malignancy like ovarian cancer.…”